Multifaceted interventions for healthcare-associated infections and rational use of antibiotics in a low-to-middle-income country: Can they be sustained?

BACKGROUND: Transmission of infection between patients by health workers, and the irrational use of antibiotics are preventable causes for healthcare-associated infections (HAI) and multi-resistant organisms. A previous study implementing a hand hygiene campaign and antibiotic stewardship program significantly reduced these infections. Sustaining such interventions can be challenging. AIMS: To evaluate whether there was a sustained effect of a multifaceted infection control and antibiotic stewardship program on HAI and antibiotic use 5 years after it began.
METHODS: A prospective evaluation study was conducted over 26 months (from February 2016 to April 2018) in a teaching hospital in Indonesia, 5 years after the implementation of an antibiotic stewardship and infection control program, which was successful when initially evaluated. All children admitted to the pediatric ICU and pediatric wards were observed daily. Assessment of HAI was made based on the criteria from the Centers for Disease Control and Prevention. Assessment of rational antibiotic use was based on the WHO Pocket Book of Hospital Care for Children. Multivariable logistic regression analysis was used to quantify the relationship between the HAI and the multifaceted intervention.
RESULTS: We observed an increase in HAIs, from 8.6% (123/1419 patients) in the initial post-intervention period in 2011-2013 to 16.9% (314/1855) in the evaluation study (relative risk (RR) (95% CI) 1.95 (1.60 to 2.37)). After adjusting for potential confounders, we found that an increase in HAI in the evaluation period with adjusted OR 1.94 (95% CI 1.53 to 2.45). Inappropriate antibiotic use also increased, from 20.6% (182 of 882 patients who were prescribed antibiotics) to 48.6% (545/1855) (RR 2.35 (2.04 to 2.71)). Hand hygiene compliance also declined from 62.9% (1125/1789) observed moments requiring hand hygiene to 51% (1526/2993) (RR 3.33 (2.99 to 3.70)).
CONCLUSIONS: Healthcare-associated infections and irrational use of antibiotics remain significant even after the implementation of a multifaceted infection control intervention and antibiotic stewardship program. There is a need for continuous input, ongoing surveillance and long-term monitoring of these interventions to sustain compliance and effectiveness and address problems as they emerge.

Introduction

Morbidity and mortality of healthcare-associated infections in children in low-to-middle-income countries are significant, and these can be reduced with a program of low cost interventions [1,2]. The high burden of healthcare-associated infections and the significant effect of the interventions on both healthcare-associated infections and in-hospital mortality requires effective policy and practice responses to prevent these infections [3]. Healthcare-associated infections should never be considered as inevitable, even in settings with limited resources.

In Yogyakarta, Indonesia, we conducted surveillance for healthcare-associated infection and long-term monitoring of the effectiveness of the multifaceted intervention described in the previous published study [1]. This current study provides an evaluation of the incidence of healthcare-associated infection, irrational antibiotic use, hand hygiene compliance, and mortality to evaluate whether the effect of the multifaceted infection control intervention was sustained over 5 years.

Material and methods

Setting

The study was conducted at the Dr. Sardjito Teaching Hospital, Yogyakarta, Indonesia, in the Pediatric Intensive Care Unit (PICU) and the public general pediatric wards. The Dr. Sardjito Hospital is a referral hospital for Yogyakarta and the Southern part of the Central Java province in Indonesia, and provides services to a population of approximately 3.6 million people.

Design

A prospective cohort study evaluating whether the previous multifaceted intervention to reduce healthcare-associated infections was sustained after 5 years [1].

Inclusion criteria

Patients who were expected to remain in the pediatric wards or PICU for more than 48 hours.

Outcome measures and data collection

Data collection methods for this study were similar to a previous effectiveness study on reducing healthcare-associated infections and improving rational use of antibiotics [1].

A. Healthcare-associated infection

The definitions of healthcare-associated infection were based on the US Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN) [4,5]. Every child in the study was observed each day to see whether he/she fulfilled the CDC criteria for a healthcare-associated infection. If criteria were fulfilled, the treating medical and nursing staff were advised to collect a culture of blood, urine or other sterile sites as appropriate on the same day.

We did not have data detailing which cultures were collected based on the study surveillance definition or based on clinical suspicion of infection of the treating doctors. We included those two as one. But we did an identical data collection to diagnose nosocomial infections in both periods. Those cultures were taken when patients had signs and symptoms of infection.

B. The rational use of antibiotics

Whether antibiotic use was rational or inappropriate was assessed at the time of study entry in every patient with a community-acquired infection who was treated with antibiotics, and each day during their hospital admission. The standards for empirical antibiotic prescribing were based on the recommendations contained in the WHO Pocket Book of Hospital Care for Children [6]. Patients had antibiotic use recorded daily from their medical record. Inappropriate antibiotic use was classified according to the spectrum, dose, and duration. Inappropriate spectrum was defined if a child received antibiotics inconsistent with the standard guideline, or broader spectrum antibiotics than the recommendation, or was exposed to unnecessary therapeutic or prophylactic antibiotics. Inappropriate dose was defined if a child received antibiotics at 20% more or less than the WHO recommended dose, or if there was insufficient dosage adjustment in renal or hepatic insufficiency [7]. Inappropriate duration was defined as antibiotic used for more than 20% longer than the recommended duration in the standard without a documented reason.

C. Hand hygiene compliance

Hand hygiene compliance was defined as hand washing with antiseptic soap and water or alcohol-based hand rubs for each of the World Health Organization’s five moments for hand hygiene [8,9]. Hand hygiene compliance was achieved when there was an indication for hand hygiene and the health worker performed this correctly. Health workers (doctors and nurses) were randomly chosen for observation using a fixed time of observation (20 ± 10 minutes each). During these periods of observations the first health worker who was involved in the care of the patient was selected [10]. Direct hand hygiene observation began when the health worker entered the patient’s room or bed area and was observed during activities that involved contact with the patient or their environment and observation ended when the health worker completed the activity and left the bed space. Health workers were informed at the beginning of the project about the hand hygiene audits, but they were not told they were specifically being observed. However, they were familiar with the role of the researcher and research assistant, whose presence was not hidden within the ward environment.

Validation of bacterial culture as a measure of healthcare-associated infection. We used standard culture techniques that had been validated in our hospital using BACTEC® 9120 (BD Diagnostics, Sparks, MD, USA). Bacterial isolation and antibiotic susceptibility testing were performed according to Clinical Pathology standard procedures [11]. For each positive result, the type of isolated organism, number of positive culture sites, time to culture positivity, the presence of focal or generalized clinical signs of infection and an overall assessment of illness were recorded. This enabled an assessment of whether the isolate was a true pathogen or a contaminant [12].

Multifaceted intervention

During 2013 to 2018, the infection control and antibiotic stewardship program had been continually implemented using the same model as in the previous published study [1]. The hospital had also achieved accreditation from the Joint Commission International (https://www.jointcommissioninternational.org). The requirement of this accreditation includes developing and implementing a program for infection control and antibiotic stewardship.

The infection control and antibiotic stewardship team consist of infectious disease doctors, specialist doctors, nurses, the pharmacist and clinical pathology and microbiology staff. We have no protected time for infection control and antibiotic stewardship nor do health care professionals involved receive additional salary for these roles.

Activities to contain healthcare-associated infections and irrational antibiotic use in Dr Sardjito Hospital included: (1) Establishing effective hospital therapeutics committees with the responsibility for overseeing antibiotic use; (2) developing guidelines for antibiotic treatment and prophylaxis and antibiotic formularies; (3) monitoring antibiotic use and feedback to prescribers; (4) establishing infection control programs for effective management of antibiotic resistance; (5) ensuring performance and quality assurance of pathogen identification and antibiotic susceptibility tests; and (6) controlling and monitoring pharmaceutical company promotional activities.

In the post-intervention and evaluation phase the team collected surveillance data on healthcare-associated infection and antibiotic use prospectively, but the surveillance did not become fully incorporated into routine quality activities. We did not have team conducting active surveillance; they collected data by passive surveillance of identified healthcare-associated infection. The hospital did not perform surveillance of antibiotic use and rational use of antibiotics. While some educational activities were conducted, audit-feedback activities were not.

Some monitoring of antibiotic use was continued routinely in the follow-up phase. For example, we discussed pediatric patients with antibiotic-related problems every week in the wards and PICU. We monitored and reported on pathogens identified and antibiotic susceptibility every 3 to 6 months. We also restricted certain antibiotics such as carbapenems, so that these antibiotics needed approval by an Antibiotic Stewardship Committee. However, monitoring antibiotic use and feedback to prescribers were not done routinely. The detailed interventions in the intervention, post-intervention, and evaluation periods were described in Table 1.

Table 1

Interventions and activities done in each period of the study.

	Intervention period (December 2010 to February 2011)	Post-intervention period (March 2011 –February 2013) and Evaluation period (February 2016 –February 2018)
Type of intervention	Educational seminars, reminders (handy module, CD, antibiotic chart), audit, and performance feedback	Ongoing education was provided where needed
Timing of interventions	Seminars were conducted at least twice for each topic for one hour, to cover all the health workers on different shifts.	Seminars were conducted only when there were new staff, pediatric residents, or medical clerkship students.
	The surveillance or audit data were collected prospectively and fed back to the health workers individually and were presented at the monthly meetings.	The surveillance or audit data were collected prospectively, but not fed back to the health workers.
Hand hygiene	Hand hygiene campaign was done routinely.	Hand hygiene campaign was done routinely.
		The hospital had achieved accreditation from the Joint Commission International
Resources for hand hygiene	A bottle of alcohol hand rub using WHO recommended formula had already been made available in every patient care room and another bottle was placed at the entrance of each room.	A bottle of alcohol hand rub using WHO recommended formula had already been made available in every patient care room and another bottle was placed at the entrance of each room.
	There was a water sink and antiseptic soap in every ward.	There was a water sink and antiseptic soap in every ward.
Antibiotic stewardship program	Activities to contain nosocomial infections and irrational antibiotic use included: (1) Establishing effective hospital therapeutics committees with the responsibility for overseeing antibiotic use; (2) developing guidelines for antibiotic treatment and prophylaxis and antibiotic formularies; (3) monitoring antibiotic use and feedback to prescribers; (4) establishing infection control programs for effective management of antibiotic resistance; (5) ensuring performance and quality assurance of pathogen identification and antibiotic susceptibility tests; and (6) controlling and monitoring pharmaceutical company promotional activities.	Activities to contain nosocomial infections and irrational antibiotic use included: (1) Establishing effective hospital therapeutics committees with the responsibility for overseeing antibiotic use; (2) developing guidelines for antibiotic treatment and prophylaxis and antibiotic formularies; (3) monitoring antibiotic use and feedback to prescribers; (4) establishing infection control programs for effective management of antibiotic resistance; (5) ensuring performance and quality assurance of pathogen identification and antibiotic susceptibility tests; and (6) controlling and monitoring pharmaceutical company promotional activities.
Timing of antibiotic stewardship program	Discussion on pediatric patients with antibiotic-related problems every week in the wards or PICU, antibiotic restriction, and monitoring antibiotic use and feedback to prescribers were done routinely.	Discussion on pediatric patients with antibiotic-related problems every week in the wards or PICU was routinely done. Antibiotic restriction was routinely implemented.
	Monitoring pathogen identification and antibiotic susceptibility tests were reported every 3 to 6 months.	Monitoring pathogen identification and antibiotic susceptibility tests were reported every 3 to 6 months.
		Monitoring antibiotic use was done prospectively, but feedback to prescribers were not done routinely.
Other measures	Measures to prevent nosocomial bloodstream infections, ventilator-associated pneumonia, and catheter-associated urinary tract infections were implemented.	Measures to prevent nosocomial bloodstream infections, ventilator-associated pneumonia, and catheter-associated urinary tract infections were implemented.
Composition/staffing of the infection control and antimicrobial stewardship programs	Infectious disease doctors, specialist doctors, nurses, the pharmacist and clinical pathology and microbiology staff. No protected time for infection control and antibiotic stewardship nor do health care professionals involved receive additional salary for these roles.	Infectious disease doctors, specialist doctors, nurses, the pharmacist and clinical pathology and microbiology staff. No protected time for infection control and antibiotic stewardship nor do health care professionals involved receive additional salary for these roles.

Outcome measures

The primary outcome was the incidence of patients with healthcare-associated infection. The incidence rate of healthcare-associated infection is reported according to two standard metrics: number of patients who developed a healthcare-associated infection/100 patients (the proportion of patients who developed a healthcare-associated infection) and healthcare-associated infection episodes/1000 patient-days.

Secondary outcomes were the proportions of patients who were exposed to the irrational use of antibiotics; hand hygiene compliance among healthcare workers; and all-cause in mortality rates.

Data analysis

After transfer into Excel, data were analyzed using STATA version 12.1 (StataCorp LP, Texas). The χ2 statistic was used to analyze the results when comparing proportions from both periods. A probability value < 0.05 was considered to denote statistical significance. The relative risk (RR) was calculated to compare the effect of the interventions between both periods by calculating the ratio of the probability of an outcome in the post-intervention period to the probability of an outcome in the evaluation period. Multivariable logistic regression analysis was used to quantify the relationship between the healthcare-associated infection and the multifaceted intervention allowing for statistical control of potential confounders including age, sex, the presence of syndrome, immunocompromised condition, referral patient, sepsis, and malnutrition. These variables were added stepwise and included in the model when having a probability value of < 0.10. The Ethics Committees of the Universitas Gadjah Mada approved the study. The ethics committee did not require individual patient consent, but all parents of children were informed of the study.

Results

A total of 1855 patients were recruited during the follow-up evaluation period from February 2016 to April 2018. Patients in the post-intervention and the follow-up evaluation periods were similar with regard to age, proportion admitted to ICU, and some underlying diseases, although there was a higher proportion of patients referred from another hospital during the follow-up period (Table 2).

Table 2

Baseline characteristics of patients in the post-intervention and the evaluation period.

Characteristics	Post-intervention n = 1419 (%)	Evaluation period n = 1855 (%)
Male sex–n (%)	797 (56.1)	943 (50.8)
Age–n (%)
≤ 12 months	351 (24.7)	483 (26.1)
> 12–60 months	365 (25.7)	479 (25.8)
> 60–120 months	327 (23.0)	366 (19.7)
> 120 months	376 (26.5)	527 (28.4)
Source of patients–n (%)
Community	835 (58.8)	774 (41.7)
Referral patients	492 (34.6)	975 (52.6)
Transferred from other units within hospital	92 (6.4)	106 (5.7)
Ward or setting–n (%)
PICU	281 (19.8)	286 (15.4)
General pediatric wards
Infectious ward	450 (31.7)	538 (29)
Non-infectious ward	688 (48.4)	1031 (55.6)
Underlying diseases–n (%)
Neurology	229 (16.1)	338 (18.2)
Nephrology	121 (8.5)	179 (9.7)
Respiratory	169 (11.9)	153 (8.3)
Cardiovascular	187 (13.1)	478 (25.8)
Hematology and oncology	177 (12.4)	17 (0.9)
Gastrohepatology	147 (10.3)	236 (12.7)
Infectious	89 (6.2)	209 (11.3)
Immunology	107 (7.5)	123 (6.6)
Sepsis	71 (5)	49 (2.6)
Endocrinology	22 (1.5)	26 (1.4)
Malnutrition	12 (0.8)	7 (0.4)
Surgery	88 (6.2)	40 (2.2)

The post-intervention period was from March 2011 to February 2013. The evaluation period was from February 2016 to April 2018.

The incidence of healthcare-associated infection

The risk of a patient developing a healthcare-associated infection increased from 8.6% (95% confidence intervals [CI] 7.3–10.2%) in the post-intervention period to 16.9% in the follow-up evaluation period: RR 1.95 (95% CI 1.60–2.37) (Table 3). There was an increase in the incidence rate of healthcare-associated infection from 9.3 per 1000 patient days (125/13498) to 20.1 infections per 1000 patient-days (416/20672). Healthcare-associated infection rates had increased 5 years after the initiation of what initially was a successful multifaceted intervention (Fig 1).

Table 3

The incidence of healthcare-associated infection over the study period.

	Incidence of HAI		Relative risk (95%CI)
	Post-intervention (%)	Evaluation (%)
Pediatric ICU	48/281 (17)	76/286 (26.6)	1.55 (1.13–2.14)
General infectious ward	44/450 (9.7)	100/530 (18.7)	1.93 (1.38–2.68)
General non-infectious ward	31/688 (4.5)	138/1038 (13.4)	2.95 (2.02–4.30)
Overall	123/1419 (8.6)	314/1855 (16.9)	1.95 (1.60–2.37)

HAI = healthcare-associated infection

The relative risk was derived by calculating the ratio of the probability of an outcome in the post-intervention period to the probability of an outcome in the evaluation period.

The post-intervention period was from March 2011 to February 2013. The evaluation period was from February 2016 to April 2018

Fig 1

The proportion of healthcare-associated infections in the intervention and post-intervention era (December 2011 to February 2013) and the follow up evaluation era (started in February 2016), the gap between those periods is indicated with the red line.

After adjusting for potential confounders, we found an increase in healthcare-associated infections in the evaluation period with adjusted OR 1.94 (95% CI 1.53 to 2.45).

The incidence of healthcare-associated bloodstream infection was 92/1419 (6.5%) among all recruited children and 92/123 (74.8%) among children with healthcare-associated infection in the post intervention period, while in the evaluation period was 36/1885 (1.9%) among all recruited children or 36/314 (11.5%) among children with healthcare-associated infection. In the post-intervention period, the most common organism related to healthcare-associated infection was Pseudomonas aeruginosa, while in the evaluation period was Klebsiella pneumoniae.

The irrational use of antibiotics

The overall use of antibiotics was not different in the post-intervention and follow-up evaluation periods; these were prescribed for 62.2% (882/1419) and 60.5% (1122/1855) of all patients respectively (p = 0.33). However, compared with the post-intervention period, in the follow-up evaluation period the risk of patients being exposed to irrational or inappropriate antibiotics increased from 20.6% (182/882) to 48.6% (545/1855), respectively, with RR 2.35 (95% CI 2.04–2.71) (Table 4).

Table 4

The incidence of antibiotic use and irrational use of antibiotics over the study period.

	Pediatric ICU		Relative risk (95%CI)	Infectious ward		Relative risk (95%CI)	Non-infectious ward		Relative risk (95%CI)	Overall		Relative risk (95% CI)
	Post n = 281(%)	Evaluation n = 286(%)		Post n = 450(%)	Evaluation n = 538 (%)		Post n = 688(%)	Evaluation n = 1031(%)		Post n = 1419(%)	Evaluation n = 1855(%)
Number of patients with antibiotics	258	219		340	365		284	538		882	1122
Number of patients exposed to incorrect or inappropriate antibiotics	93 (36)	172 (78.5)	2.18 (1.82–2.59)	52 (15.3)	192 (52.6)	3.44 (2.63–4.49)	37 (13)	181 (33.6)	2.58 (1.87–3.56)	182 (20.6)	545 (48.6)	2.35 (2.04–2.71)
- Inappropriate spectrum	89	162		52	173		34	175		175	510
- Incorrect dose	0	10		0	19		2	6		2	35
- Inappropriate duration	1	0		0	0		0	0		1	0

The relative risk was derived by calculating the ratio of the probability of an outcome in the post-intervention period to the probability of an outcome in the evaluation period.

The post-intervention period was from March 2011 to February 2013. The evaluation period was from February 2016 to April

The compliance of hand hygiene among health workers

Hand hygiene compliance decreased significantly in the follow-up evaluation period in PICU and the general non-infectious wards (Table 5). Overall hand hygiene compliance among the healthcare workers in the evaluation period decreased from 62.9% (1125/1789) to 51% (1526/2993) (p<0.001).

Table 5

The hand hygiene compliance among healthcare workers over the study period.

	Compliance with hand hygiene		p value	Relative risk (95%CI)
	Post-intervention (%)	Evaluation (%)
Pediatric ICU	390/625 (62.4)	271/714 (37.9)	< 0.001	0.61 (0.54–0.68)
General infectious ward	356/598 (59.5)	575/1050 (54.8)	0.056	0.92 (0.84–1.00)
General non-infectious ward	379/566 (66.9)	680/1229 (55.3)	< 0.001	0.83 (0.77–0.90)
Overall	1125/1789 (62.9)	1526/2993 (51)	<0.001	0.81 (0.77–0.85)

The relative risk was derived by calculating the ratio of the probability of an outcome in the post-intervention period to the probability of an outcome in the evaluation period.

The post-intervention period was from March 2011 to February 2013. The evaluation period was from February 2016 to April 2018.

Mortality

The risk of in-hospital mortality among children in the hospital decreased by 26% in the follow-up evaluation period compared to the post-intervention period, from 8.0% (114/1419) to 6.9% (113/1855) with RR 0.74 (95% CI 0.57–0.97). Mortality in children with healthcare-associated infection was 4.1% (13/314) in the evaluation period. Mortality associated with healthcare-associated infection was markedly lower in this evaluation period compared to the mortality in the post-intervention period of 24.5%.

Discussion

Major findings

Surveillance of healthcare-associated infection and the irrational use of antibiotics was conducted to determine whether the program instituted in 2010–2013 had a sustained effect on rates of healthcare-associated infection and the irrational use of antibiotics in our large teaching hospital [1]. Although the infection control program had become an integral part of the health culture in our hospital, this current study showed that the clinical impact of the multi-faceted infection prevention strategy was not fully sustained. There were no major differences in the patient population in the two time periods, and even after adjusting for differences, there was increase in healthcare-associated infections.

The trend of healthcare-associated infection rates had increased 5 years after the initiation of the multifaceted intervention, despite the program being highly successful in the first 18 months of detailed observation. The cumulative incidence of healthcare-associated infection in the current era study population was 16.9% of patients surveyed, with an incidence rate of 20.1 infections per 1000 patient-days; higher than in the same setting after initiating a multifaceted intervention on infection control and antibiotic stewardship program 5 years before. The earlier multifaceted intervention had brought the incidence down to 8.7% or 9.3 infections per 1000 patient-days [1]. Staff turnover and health care shortages create problems because new doctors and nurses were not aware of infection control bundle especially in PICU. Increasing nurse-to-patient ratios have been associated with the spread of infection. Further, nurse shortages are also related to increased risk of healthcare-associated infections [13].

The irrational use of antibiotic was high compared to the previous published study in the same setting. Some interventions were done routinely such as restricting antibiotic availability by our Antibiotic Stewardship Committee, so that they had to approve use of expensive broad-spectrum agents. Weekly review of antibiotic use for 1–2 patients in wards and PICU was also done. However, antibiotic stewardship rounds as an active process for all patients on antibiotics were not performed routinely. Further, monitoring of antibiotic use and feedback to prescribers were also not done routinely. In our pediatric wards and PICU we indeed had antibiotic guidelines for many years. But our patients mostly came from other hospitals and those patients had been given “high class of antibiotics” and most doctors at our hospital considered that the antibiotics needed to be escalated. Therefore, we need to start a weekly antibiotic stewardship ward round promoting more disciplined and rational antibiotic prescribing, weekly reminders of best practice in prescribing, enforcing the rules, ceasing or scaling back antibiotics, putting in stop dates in the prescription, and enforcing the writing of indications. These activities are only effective if done routinely on a weekly basis [14].

This finding also highlights the partially sustained effect of intervention of hand hygiene campaign in our hospital. There is a need for ongoing interventions to improve the compliance of hand hygiene practice among the healthcare workers. Although the hand hygiene campaign was in place as a part of the hospital program, education for healthcare workers on the rationale for and how to conduct hand hygiene practice can reduce healthcare-associated infection, and is routinely needed to reduce potentially significant burden of infection especially in a setting like our hospital when the turnover of health workers exists.

Both overall in-hospital mortality in children in the study during this follow-up evaluation period and mortality related to healthcare-associated infection were lower in this evaluation period, compared to the previous published study [1]. One of the possible reasons for the lower mortality rates could be due to a secular trend to lower death rates in hospitals that might relate to improved overall quality of care, preventative strategies, better overall nutrition, and substantial changes in epidemiology including fewer bacterial sepsis and more viral infections [15].

Comparisons with other studies and explanation for findings

There are limited published studies on the sustainability of the effectiveness of interventions on infection control and antibiotic stewardship programs [16-18]. The multifaceted interventions needed to reduce infections and improve rational use of antibiotics have been difficult to sustain in high-income and low- and middle-income countries [15, 17, 19].

Given limited published studies on the sustainability of interventions for infection control and antibiotic stewardship, and the reasons why they were difficult to sustain the effect, we suggest 12 potential difficulties in sustaining the effect of a multifaceted intervention on infection control and antibiotic stewardship program, especially among those children in low- and middle-income countries based on our observations during this study. These include lack of performance feedback, staff turnover, message fatigue, distraction of other programs and initiatives, increased numbers of patients, increased complexity of higher-risk patients such as immune suppressed children, increased referred patients from outside hospitals, loosening of antibiotic prescribing standards over time, lack of consistency or intensity of input or reduction in frequency of training, lack of senior leadership input on this matter, never quite reaching the threshold of control of multi resistance organisms, and availability of resources such as hand hygiene and guidelines.

Previous studies indicate that quality improvement interventions need to be a continuous, flexible and evolving [16-19]. Staff turnover means that training and awareness of infection control and antibiotic stewardship program have to virtually be continuous. Continuous availability of guidelines, and standard antibiotics, and input from infection control teams as promoted by WHO guidelines in 2016 [20], need to be part of the health culture.

However, antibiotic prescribing is a complex process that is mutually and dependently influenced by patients, physicians, other healthcare providers, and the healthcare system. These most influential factors consist of intrinsic factors including physicians’ attitudes (fear of undertreating a significant infection, complacency, or perverse incentives for poor prescribing) and extrinsic factors including patient-related factors (e.g. signs and symptoms) or healthcare system-related factors (e.g. time pressure and guidelines implemented) [21].

In some settings, a behavioral change approach on hand hygiene program using ongoing frequent audit and feedback with improvement of cognitive behavior and use of immediate positive reinforcement has shown significant and sustained improvements in hand hygiene compliance at an acceptable cost [22].

Recommendations for practice and research

Infection control programs should integrate two fundamental strategies to reduce healthcare-associated infections, consisting of reducing transmission of pathogens between patients and reducing the emergence and spread of antibiotic resistance.

We have shown that simple infection control measures including hand hygiene and rational use of antibiotics, are feasible and effective in the previous study in the same setting. To better understand why there was not a fully sustained effect, a qualitative study that explores the enablers and barriers to adhering to guidelines among the healthcare workers is needed. We considered that performance and compliance of the health workers on the infection control measures might need to be fed-back on a regular basis to ensure the sustainability of the program.

An antibiotic stewardship program should include prescribing behaviour in the recommendations, guidelines and policy, by pushing prescribers to make prescribing decisions that are beneficial both to the patient and to public health. Therefore, healthcare professionals need to be involved in the decision-making process to achieve and sustain the prescribing behaviour and optimal antibiotic prescribing [19].

Since the existing antibiotic stewardship program was not enough to achieve good long-term results, there is a need to develop a more comprehensive antibiotic stewardship program for healthcare workers both in PICU and pediatric wards. This includes ongoing education for healthcare workers on the rationale for and how to achieve rational use of antibiotic practice can reduce healthcare-associated infection related to antibiotic resistant bacteria.

Strengths and Limitation

As far as we are aware, this study is the first study in a low-to-middle-income country to evaluate the sustainability of interventions to reduce healthcare-associated infections and irrational use of antibiotic in children, which is very common problem in such settings. A limitation of this study is a gap exists in the time period of intervention study in ending February 2013 and beginning February 2016 when the evaluation study was started, so that it is not continuous time period. We considered that ascertainment bias might occur in this study. But in this study, we addressed the potential for ascertainment bias in several ways. First, we did an identical data collection to diagnose healthcare-associated infections in both periods. Further, there were no changes in laboratory procedures between both periods that might falsify the culture results in the evaluation period tended to be positive. These relatively independent factors suggest that the identification of healthcare-associated infections between two periods was similar.

Conclusions

This evaluation study showed the high burden of healthcare-associated infection and irrational use of antibiotics in children in our hospital remained even after implementing a multifaceted intervention to reduce healthcare-associated infection and irrational use of antibiotics. Possible reasons why it was difficult to sustain the effect of multifaceted intervention on infection control and antibiotic stewardship program to prevent healthcare-associated infections include lack of performance feedback or how and why were the antibiotic prescribing standards loosened. Ongoing surveillance and long-term monitoring of such programs at a level of intensity that includes weekly input is needed to sustain the effect in settings with limited resources. The multifaceted infection control and antibiotic stewardship program should involve healthcare professionals in the decision-making processes, involve small group problem solving, and use positive reinforcement in order to sustain compliance and effectiveness.

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12 Nov 2019

PONE-D-19-24025

An evaluation of multifaceted interventions on hospital acquired infections and rational use of antibiotics in a developing country setting: Can they be sustained?

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2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

Additional Editor Comments (if provided):

1. Please provide a table which describes the interventions and programs in place in the original post-intervention and in the follow-up evaluation phase. This should include (briefly) the composition/staffing of the infection control and antimicrobial stewardship programs in each phase. This information is critical to help the reviewer understand the potential reasons for increases in HAIs

2. The basis for Table 5 is unclear: is this based on the literature or your observations in your facility and program? Recommend deleting, and including some of these elements in the Table describing the interventions and program in each phase (e.g., senior leadership input and support, resources for hand hygiene etc.)

3. The type of regression analyses used needs to be specified.

4. Tables should have more descriptive and meaningful titles. For example, Table 1. Baseline characteristics of ?? in post-intervention and evaluation period. Add footnotes defining post-intervention and evaluation period with dates added to the column headers or footnote. All tables with measures of relative risk/odds ratio should have the statistical method used to derive those also stated as table footnote.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Overall, this is an important topic addressed by authors-- maintenance of HAI and antimicrobial stewardship interventions after an initial intervention. Clearly, the authors have put a lot of work into getting this data and reporting upon it in this hospital in Indonesia.

I have several comments that I think would overall strengthen the paper and make it more likely to meet requirements to be published in something like PLOS One.

Abstract: It is unclear in the abstract what the actual intervention was and what was done in the maintenance phase -- this is unclear in the paper as well. This should be delineated in the abstract for the reader.

Throughout the paper, I would use healthcare-associated infection rather than hospital acquired and rather than nosocomial as per current HAI lingo.

Methods: the methods should clearly outline the interventions and the surveillance interventions --after reading and re reading the paper, I'm not sure what happened during the intervention versus what happened in the maintenance phase. More helpful than the tables presented would be a timeline of the initial intervention and what continued in the maintenance phase. (would replace table 5 which should all be in the discussion instead with this timeline instead)

In the methods, the authors defined inappropriate duration of antibiotics as more than 20% longer than the recommended duration (according to what? and also have other studies used this definition? if yes, would cite.)

In methods, I'd like to know more details about the IC and Abx stewardship team. Who made up each team? Was there a MD on both? What members are on the stewardship team, if there isnt a team then on the committee. Did anyone have protected time for IC or for stewardship or get money for these roles?

These details are important in international IC and stewardship studies.

Results:

Would give overall HAI but also individual HAI numbers as possible (which HAIs were you looking at, which seemed to increase the most?-- would add a lot to the paper)

For hand hygiene compliance, would add the total number of observations into the paper.

Is there a way to measure case mix index in the two periods for the mortality results?

Discussion

The discussion is wordy but doesn't get at the meat of the paper.

Again, I was struck that I didnt understand the intervention vs maintenance phase well--- this needs to be much clearer in this paper and will help frame the discussion.

What pieces of the maintenance phase if any do authors think are helping, what should be strengthened, what could particularly help if the leadership was going to invest into one specific area?

How could the CDC core elements of stewardship for limited resource settings help? This whole discussion should be streamlined and identify things that could happen in the maintenance phase that would be high yield (would do some of a lit search to help inform this)

Reviewer #2: The manuscript entitled “an evaluation of multifaceted interventions on HAI and rational use of antibiotics in a developing country setting: can they be sustained?” is a prospective cohort observational study and a follow-up of a study published in 2015.

The authors conducted surveillance of HAI and AMU 5 years after implementing an infection control bundle and a stewardship program at hospital in Indonesia.

The initial 2015 study had shown benefits of this bundle in terms of outcomes: the authors noted decreased incidence of HAI, decreased mortality, and a higher proportion of appropriate AMU (though no decrease in total AMU). In this follow-up study, they note that rates of HAI and inappropriate AMU had increased (close to the baseline pre-intervention rates), though mortality was stable or had slightly decreased.

In this reviewer's opinion the topic of sustainability (and cost-effectiveness) of interventions to reduce HAI and AMR is very pertinent for LMICs, and certainly worthy of publication. The authors should be commended for tackling this follow-up study, after significants efforts to implement the intervention some. years ago. Though this paper has merit, because it mostly describes follow-up surveillance data (using identical methods and analysis and without additional interventions), in this reviewer's opinion a concise communication might be preferable to a full text article.

Additional concerns are provided in more detail below, in the hope they can be helpful for the authors.

Major concerns:

- In the 2015 paper from the same authors, the intervention appears to be an “intensive intervention with HH, educational sessions, and audit-feedback for antimicrobial use (AMU)” for 3 months, then a period of “post-intervention” during which effectiveness of the bundle was measured in terms of incidence of HAI and AMU. In this paper, the authors have compared the data from the previous study (post-intervention phase)with data from the follow-up phase, but what is missing is data on the sort of activities which were (or were not) occurring. The paper is entitled “sustainability of interventions” , but the data provided that does not clearly support that it was the absence of interventions that led to the increased rates. Few details are provided on monitoring of activities: what sort of indicators were used to determine that certain activities were sustained but not others (eg: KPI?). It would also be helpful to clarify whether the research team was collecting surveillance data prospectively or if surveillance had become fully incorporated into routine quality activities, and was conducted by a different group of individuals in the follow-up phase. The discussion alludes to the fact that the hospital culture had changed and some activities were conducted, but audit-feedback activities were no longer conducted. Was this also not the case in the initial post-intervention phase (2015?). This whole aspect is somewhat confusing and should be clarified in the methods section – or, the manuscript significantly shortened to a concise communication simply stating that 5 years after implementing a bundle consisting of Infection Control Program and a Stewardship program, rates of HAI had increased.

- HAI rates increased but mortality decreased in the follow-up phase: the authors argue this may be due to overall improved quality of care, but they also attribute increased HAI rates to worse practices and high staff turnover, so there is an inherent contradiction. Further, no details are provided on whether this was all-cause mortality, in hospital mortality, 30-day mortality, etc and most importantly, what was the mortality attributable to infection in both these groups? is it possible that mortality was lower because of the use of broad spectrum antibiotics? Was selection/ascertainment bias involved in this?

- Since a lot of effort went into identifying HAI based on microbiology and clinical findings, data on characteristics and types of HAI (number of cases of HAP, UTI, CLABSI etc) (as well as a description of who did the surveillance) would be helpful to better understand shifts in epidemiology and increasing rates over time.

- Also, it appears antibiograms were collected every 6 months: if available, this data should be provided (at least for some organisms that are relevant for HAI) so we can assess evolving rates of drug-resistance over time, and attempt to correlate with AMU, mortality etc.

- The discussion is largely speculative, and lists solutions that are not linked to the findings of the study. it would be more useful to point to specific lessons learned that other centres in LMICs can learn from, rather than provide a list of recommendations and best practices which are very generic. For example, did the group identify specific barriers to sustaining audit-feedback over time? The authors should elaborate much more on the limitations of the study – in particular discuss possible selection and ascertainment bias.

- Table 5 is unnecessary and repeats much of what was said in discussion.

- The reference that was provided for treatment guidelines is the 2005 WHO guideline: was that really the guideline used by clinicians in the hospital until 2018? If so, the impact of outdated guidelines on clinical practice should be addressed and the authors should consider revising their assessment of appropriate vs inappropriate antibiotic prescriptions?

- Same comment for the CLSI guidelines (2007) – is that really what the laboratory was using? These are updated every year with some major revisions in susceptibility breakpoints in the past 12 years. Please review.

Minor points

- An operational definition for the 2 periods should be provided and specify exactly the duration of each, as well as what activities were occurring when

- Table 2, 3 and 4 should not be entitled “sustainability of intervention..” which is an interpretation – the titles should be neutral and refer to what is shown (eg: rates of HAI over the study period, ..

The term "developing country" should be revised to the more appropriate LMIC, or other term that is now more in use, and used consistently throughout the text.

- The text should be revised for clarity and flow, and some sentences should be re-structured.

**********

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

31 Dec 2019

Response to Reviewer

Journal Requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: Thank you so much. Yes, we have revised accordingly.

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

Response: Yes, we have added the information about patient consent because we only collected routine data without intervening. The ethics committee did not require individual patient consent, but all parents of children were informed of the study.

Additional Editor Comments (if provided):

1. Please provide a table which describes the interventions and programs in place in the original post-intervention and in the follow-up evaluation phase. This should include (briefly) the composition/staffing of the infection control and antimicrobial stewardship programs in each phase. This information is critical to help the reviewer understand the potential reasons for increases in HAIs

Response: Yes, we have added a table which describes the interventions in each period of the study.

2. The basis for Table 5 is unclear: is this based on the literature or your observations in your facility and program? Recommend deleting, and including some of these elements in the Table describing the interventions and program in each phase (e.g., senior leadership input and support, resources for hand hygiene etc.)

Response: The table was based on our observations in my facility and program, we considered to delete and included these elements in the Table describing intervention and in the Discussion section.

3. The type of regression analyses used needs to be specified.

Response: We did not use regression analysis in this analysis and we have deleted this from the manuscript.

4. Tables should have more descriptive and meaningful titles. For example, Table 1. Baseline characteristics of ?? in post-intervention and evaluation period. Add footnotes defining post-intervention and evaluation period with dates added to the column headers or footnote. All tables with measures of relative risk/odds ratio should have the statistical method used to derive those also stated as table footnote.

Response: Yes, we have revised the description of Table 1. We have added footnotes about the relative risk (RR) that was calculated to compare the effect of the interventions between both periods by calculating the ratio of the probability of an outcome in the post-intervention period to the probability of an outcome in the evaluation period, the time of both periods.

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Overall, this is an important topic addressed by authors-- maintenance of HAI and antimicrobial stewardship interventions after an initial intervention. Clearly, the authors have put a lot of work into getting this data and reporting upon it in this hospital in Indonesia.
I have several comments that I think would overall strengthen the paper and make it more likely to meet requirements to be published in something like PLOS One.

Abstract: It is unclear in the abstract what the actual intervention was and what was done in the maintenance phase -- this is unclear in the paper as well. This should be delineated in the abstract for the reader.

Response: Thank you so much for the suggestions.

We have provided a table which describes the interventions in each period (Table 1).

Throughout the paper, I would use healthcare-associated infection rather than hospital acquired and rather than nosocomial as per current HAI lingo.

Y

Response: Yes, we have revised accordingly.

Methods: the methods should clearly outline the interventions and the surveillance interventions --after reading and re reading the paper, I'm not sure what happened during the intervention versus what happened in the maintenance phase. More helpful than the tables presented would be a timeline of the initial intervention and what continued in the maintenance phase. (would replace table 5 which should all be in the discussion instead with this timeline instead)

Response: Yes, we have provided a table which describes the interventions during the intervention, the post-intervention, and the evaluation periods. The content of this table was based on our observations in my facility and program, we considered to delete Table 5. We decided to include these to the Discussion section in order to explain the reason why it was difficult to sustain the effect of interventions.

In the methods, the authors defined inappropriate duration of antibiotics as more than 20% longer than the recommended duration (according to what? and also have other studies used this definition? if yes, would cite.)

Response: We used this criteria in our previous study (the intervention study).

In methods, I'd like to know more details about the IC and Abx stewardship team. Who made up each team? Was there a MD on both? What members are on the stewardship team, if there isnt a team then on the committee. Did anyone have protected time for IC or for stewardship or get money for these roles?
These details are important in international IC and stewardship studies.

The infection control and antibiotic stewardship team consist of infectious disease doctors, specialist doctors, nurses, the pharmacist and clinical pathology and microbiology staff. We have no protected time for infection control and antibiotic stewardship nor get money for these roles. 

Results:
Would give overall HAI but also individual HAI numbers as possible (which HAIs were you looking at, which seemed to increase the most?-- would add a lot to the paper)

Response: We considered to publish this separately. For hand hygiene compliance, would add the total number of observations into the paper. The total number of observation in the evaluation period was 2993 (Table 5). Overall hand hygiene compliance among the healthcare workers in the evaluation period decreased from 62.9% (1125/1789) to 51% (1526/2993) (p<0.001)

Is there a way to measure case mix index in the two periods for the mortality results?

Response: In this present study, we did not apply the case mix risk adjusted in-hospital mortality.

Discussion

The discussion is wordy but doesn't get at the meat of the paper.
Again, I was struck that I didnt understand the intervention vs maintenance phase well--- this needs to be much clearer in this paper and will help frame the discussion.
What pieces of the maintenance phase if any do authors think are helping, what should be strengthened, what could particularly help if the leadership was going to invest into one specific area?

Response: We have provided Table 1 of interventions in each period of the study. We considered that performance and compliance of the health workers on the infection control measures might need to be feed back to them in a regular basis to ensure the sustainability of the program.

How could the CDC core elements of stewardship for limited resource settings help? This whole discussion should be streamlined and identify things that could happen in the maintenance phase that would be high yield (would do some of a lit search to help inform this)

Response: We did a systematic review on the prevention of HAI which concludes that hand hygiene and antibiotic stewardship program could reduce HAI up to 50%. Therefore, these measures should be conducted simultaneously. But performance and compliance of the health workers on these measures might need to be feed back to them in a regular basis to ensure the sustainability of the program (Paediatr Int Child Health 2013;33(2):61-78).

Reviewer #2: The manuscript entitled “an evaluation of multifaceted interventions on HAI and rational use of antibiotics in a developing country setting: can they be sustained?” is a prospective cohort observational study and a follow-up of a study published in 2015.
The authors conducted surveillance of HAI and AMU 5 years after implementing an infection control bundle and a stewardship program at hospital in Indonesia.
The initial 2015 study had shown benefits of this bundle in terms of outcomes: the authors noted decreased incidence of HAI, decreased mortality, and a higher proportion of appropriate AMU (though no decrease in total AMU). In this follow-up study, they note that rates of HAI and inappropriate AMU had increased (close to the baseline pre-intervention rates), though mortality was stable or had slightly decreased.

In this reviewer's opinion the topic of sustainability (and cost-effectiveness) of interventions to reduce HAI and AMR is very pertinent for LMICs, and certainly worthy of publication. The authors should be commended for tackling this follow-up study, after significants efforts to implement the intervention some. years ago. Though this paper has merit, because it mostly describes follow-up surveillance data (using identical methods and analysis and without additional interventions), in this reviewer's opinion a concise communication might be preferable to a full text article.

Additional concerns are provided in more detail below, in the hope they can be helpful for the authors.

Major concerns:

- In the 2015 paper from the same authors, the intervention appears to be an “intensive intervention with HH, educational sessions, and audit-feedback for antimicrobial use (AMU)” for 3 months, then a period of “post-intervention” during which effectiveness of the bundle was measured in terms of incidence of HAI and AMU. In this paper, the authors have compared the data from the previous study (post-intervention phase) with data from the follow-up phase, but what is missing is data on the sort of activities which were (or were not) occurring. The paper is entitled “sustainability of interventions”, but the data provided that does not clearly support that it was the absence of interventions that led to the increased rates. Few details are provided on monitoring of activities: what sort of indicators were used to determine that certain activities were sustained but not others (eg: KPI?). It would also be helpful to clarify whether the research team was collecting surveillance data prospectively or if surveillance had become fully incorporated into routine quality activities, and was conducted by a different group of individuals in the follow-up phase. The discussion alludes to the fact that the hospital culture had changed and some activities were conducted, but audit-feedback activities were no longer conducted. Was this also not the case in the initial post-intervention phase (2015?). This whole aspect is somewhat confusing and should be clarified in the methods section – or, the manuscript significantly shortened to a concise communication simply stating that 5 years after implementing a bundle consisting of Infection Control Program and a Stewardship program, rates of HAI had increased.

Response: Thank you so much for the suggestion. Yes, the research team was collecting surveillance data prospectively, but the surveillance had not become fully incorporated into routine quality activities in the post-intervention and follow-up phase. The hospital did not have team to do active surveillance, they collect data by doing passive surveillance of healthcare-associated infection but not routinely. The hospital did not do surveillance of antibiotic use and rational use of antibiotics. The hospital culture had changed and some activities were conducted, but audit-feedback activities were no longer conducted. This was also the case in the initial post-intervention phase.

- HAI rates increased but mortality decreased in the follow-up phase: the authors argue this may be due to overall improved quality of care, but they also attribute increased HAI rates to worse practices and high staff turnover, so there is an inherent contradiction. Further, no details are provided on whether this was all-cause mortality, in hospital mortality, 30-day mortality, etc and most importantly, what was the mortality attributable to infection in both these groups? is it possible that mortality was lower because of the use of broad spectrum antibiotics? Was selection/ascertainment bias involved in this?

Response: The mortality rate was all-cause in hospital mortality. Mortality in children with healthcare-associated infection was 4.1% (13/314). Mortality related to healthcare-associated infection was markedly lower in this evaluation period compared to the mortality in the post-intervention period of 24.5%.

We considered that ascertainment bias might occur in this study. But in this study, we addressed the potential for ascertainment bias in several ways. First, we did an identical data collection to diagnose healthcare-associated infections in both periods. Further, there were no changes in laboratory procedures between both periods that might falsify the culture results in the evaluation period tended to be positive. These relatively independent factors suggest that the identification of healthcare-associated infections between two periods was similar.

- Since a lot of effort went into identifying HAI based on microbiology and clinical findings, data on characteristics and types of HAI (number of cases of HAP, UTI, CLABSI etc) (as well as a description of who did the surveillance) would be helpful to better understand shifts in epidemiology and increasing rates over time.

Response: The surveillance of HAI was done by the research team not incorporated with the hospital program. The detailed HAI in the evaluation period will be published later, but the incidence of nosocomial bloodstream infection in the post intervention period was 92/1419 (6.5%) among all recruited children and 92/123 (74.8%) among children with HAI, while in the evaluation period was 36/1885 (1.9%) among all recruited children or 36/314 (11.5%) among children with HAI. We considered that although the proportion of HAI increased, the severity of HAI decreased. So that the mortality associated with HAI also decreased, from 25.5% to 4.1%, in the post-intervention period and the evaluation period, respectively.

- Also, it appears antibiograms were collected every 6 months: if available, this data should be provided (at least for some organisms that are relevant for HAI) so we can assess evolving rates of drug-resistance over time, and attempt to correlate with AMU, mortality etc.

Response: In the post-intervention period, the most common organism related to HAI was Pseudomonas aeruginosa, while in the evaluation period was Klebsiella pneumoniae.

- The discussion is largely speculative, and lists solutions that are not linked to the findings of the study. it would be more useful to point to specific lessons learned that other centres in LMICs can learn from, rather than provide a list of recommendations and best practices which are very generic. For example, did the group identify specific barriers to sustaining audit-feedback over time? The authors should elaborate much more on the limitations of the study – in particular discuss possible selection and ascertainment bias.

Response: We considered that ascertainment bias might occur in this study. But in this study, we addressed that issue of ascertainment bias in several ways. First, we did an identical data collection to diagnose healthcare-associated infections in both periods. Further, there were no changes in laboratory procedures between both periods that might falsify the culture results in the evaluation period tended to be positive. These relatively independent factors suggest that the identification of healthcare-associated infections between two periods was similar.

- Table 5 is unnecessary and repeats much of what was said in discussion.

Response: Yes, we have deleted Table 5 and included in the discussion.

- The reference that was provided for treatment guidelines is the 2005 WHO guideline: was that really the guideline used by clinicians in the hospital until 2018? If so, the impact of outdated guidelines on clinical practice should be addressed and the authors should consider revising their assessment of appropriate vs inappropriate antibiotic prescriptions?

Response: We have updated the guidelines which used the 2013 WHO guideline.

- Same comment for the CLSI guidelines (2007) – is that really what the laboratory was using? These are updated every year with some major revisions in susceptibility breakpoints in the past 12 years. Please review.

Response: We have updated the CLSI guidelines (2015).

CLSI. Performance standards for antimicrobial susceptibility testing-seventeeth informationan supplement. CLSI document M07-A10. 2015.

Minor points
- An operational definition for the 2 periods should be provided and specify exactly the duration of each, as well as what activities were occurring when

The post-intervention era was from 1 December 2011 to 28 February 2013 and the evaluation evaluation era was started in 1 February 2016 to 30 April 2018. The activities were occurring in each period was provided in Table 1.

- Table 2, 3 and 4 should not be entitled “sustainability of intervention..” which is an interpretation – the titles should be neutral and refer to what is shown (eg: rates of HAI over the study period, ..
The term "developing country" should be revised to the more appropriate LMIC, or other term that is now more in use, and used consistently throughout the text.

Response: Yes, we have revised accordingly.

- The text should be revised for clarity and flow, and some sentences should be re-structured.

Response: Yes, we have revised accordingly.

Submitted filename: Response to Reviewer.docx

Click here for additional data file.

13 Jan 2020

PONE-D-19-24025R1

Multifaceted interventions for healthcare-associated infections and rational use of antibiotics in a low-to-middle-income country: Can they be sustained?

PLOS ONE

Dear Dr. Murni,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Thank you for making the suggested changes to your manuscript. Please address the following additional comments:

1. Under Methods section A. Hospital-acquired infection, the authors state that “The definitions of HAI were based on the US Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN). Every child in the study was observed each day to see whether he/she fulfilled the CDC criteria for a HAI. If criteria were fulfilled, the treating medical and nursing staff were advised to collect a culture of blood, urine or other sterile sites as appropriate on the same day.”

Please elaborate on this process – how many/what proportion of culture collection was guided by the study surveillance vs. based on clinical suspicion of infection? Could the variability in this process explain any of the observed increase in HAIs during the maintenance phase?

2. The authors have clarified that regression analysis was not used and there was no accounting for changes in case-mix over time. I would include in the discussion as a limitation of an analysis that it does not account for potential changes in patient characteristics over time. Please also consider a brief statement on whether any major changes in patient characteristics occurred to your knowledge e.g., change in immunocompromised host population, types of surgery etc.

3. Please proof-read to ensure that HAI is now spelled out as healthcare-associated infection throughout (some instances of use of hospital-acquired were noted)

4. Change header stating “The use of irrational antibiotics” to “The irrational use of antibiotics”

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Academic Editor

PLOS ONE

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27 Feb 2020

Dear Reviewers and Editor,

We have revised the manuscript accordingly as suggested. We have addressed the following additional comments:

1. Under Methods section A. Hospital-acquired infection, the authors state that “The definitions of HAI were based on the US Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN). Every child in the study was observed each day to see whether he/she fulfilled the CDC criteria for a HAI. If criteria were fulfilled, the treating medical and nursing staff were advised to collect a culture of blood, urine or other sterile sites as appropriate on the same day.”

Please elaborate on this process – how many/what proportion of culture collection was guided by the study surveillance vs. based on clinical suspicion of infection? Could the variability in this process explain any of the observed increase in HAIs during the maintenance phase?

Response to the Reviewer:

We did not have data detailing which cultures were collected based on the study surveillance definition or based on clinical suspicion of infection of the treating doctors. We included those two as one.

But we did an identical data collection to diagnose nosocomial infections in both periods. Those cultures were taken when patients had signs and symptoms of infection. Further, there were no changes in laboratory procedures between the post intervention and maintenance periods that might falsify the culture results. These relatively independent factors suggest that the identification of nosocomial infections between two periods was similar.

2. The authors have clarified that regression analysis was not used and there was no accounting for changes in case-mix over time. I would include in the discussion as a limitation of an analysis that it does not account for potential changes in patient characteristics over time. Please also consider a brief statement on whether any major changes in patient characteristics occurred to your knowledge e.g., change in immunocompromised host population, types of surgery etc.

Response to the Reviewer:

We decided to perform multivariable logistic regression analysis to quantify the relationship between the HAI and the multifaceted intervention allowing for statistical control of potential confounders including age, sex, the presence of syndrome, immunocompromised condition, referral patient, sepsis, and malnutrition. We add the Table 4. Multivariable analysis of the factors affecting intervention on HAI.

3. Please proof-read to ensure that HAI is now spelled out as healthcare-associated infection throughout (some instances of use of hospital-acquired were noted)

Response to the Reviewer: We have revised accordingly.

4. Change header stating “The use of irrational antibiotics” to “The irrational use of antibiotics”

Response to the Reviewer: We have revised accordingly.

Submitted filename: Response to Reviewer .docx

Click here for additional data file.

27 Apr 2020

PONE-D-19-24025R2

Multifaceted interventions for healthcare-associated infections and rational use of antibiotics in a low-to-middle-income country: Can they be sustained?

PLOS ONE

Dear Dr. Murni,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

1. Thank you for clarifying the process of culture collection. Please include this information and explanation in the methods section.

2. Thank you for adding the multivariable regression analysis. Please also do the following: a) ensure that variable names in the model are the same as the variable names in Table 2. b) Table 4 is not clear, and  likely not needed. It would be better to describe the model building process in the text itself - were the variables added stepwise, what were the criteria for including the variables in the model etc. c) The statement "We did a multivariable analysis to adjust for differences in patient characteristics." is not necessary in the Results section, it is already explained in the Methods.

3) In the discussion, when discussing major findings, I would state that there were no major differences in the patient population in the two time periods, and even after adjusting for differences, there was an increase in HAIs. Similarly, I would expand on the statement "Staff turnover and health care shortages create problems

because new doctors and nurses were not aware of infection control bundle especially in PICU." Do you think this was the major reason for the increase, please state this more clearly and expand with a couple of additional statements,

==============================

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7 May 2020

Dear Reviewers and Editor,

We have revised the manuscript accordingly as suggested. We have addressed the following additional comments:

1. Thank you for clarifying the process of culture collection. Please include this information and explanation in the methods section.

Response to the Reviewer:

Thank you. Yes, we have included this information in the Methods section.

We did not have data detailing which cultures were collected based on the study surveillance definition or based on clinical suspicion of infection of the treating doctors. We included those two as one. But we did an identical data collection to diagnose nosocomial infections in both periods. Those cultures were taken when patients had signs and symptoms of infection.

2. Thank you for adding the multivariable regression analysis. Please also do the following: a) ensure that variable names in the model are the same as the variable names in Table 2. b) Table 4 is not clear, and likely not needed. It would be better to describe the model building process in the text itself - were the variables added stepwise, what were the criteria for including the variables in the model etc. c) The statement "We did a multivariable analysis to adjust for differences in patient characteristics." is not necessary in the Results section, it is already explained in the Methods.

Response to the Reviewer:

a. Thank you, we have revised the variable name in the Table 2 is the same as the variable in the model.

b. We have deleted Table 4 and described the model in the text.

c. Yes, we have deleted and revised accordingly.

3) In the discussion, when discussing major findings, I would state that there were no major differences in the patient population in the two time periods, and even after adjusting for differences, there was an increase in HAIs. Similarly, I would expand on the statement "Staff turnover and health care shortages create problems

because new doctors and nurses were not aware of infection control bundle especially in PICU." Do you think this was the major reason for the increase, please state this more clearly and expand with a couple of additional statements

Response to the Reviewer:

Thank you, we have added the statement as suggested.

Staff turnover and health care shortages create problems because new doctors and nurses were not aware of infection control bundle especially in PICU. Increasing nurse-to-patient ratios have been associated with the spread of infection. Further, nurse shortages are also related to increased risk of healthcare-associated infections.

Submitted filename: Response to Reviewer .docx

Click here for additional data file.

22 May 2020

Multifaceted interventions for healthcare-associated infections and rational use of antibiotics in a low-to-middle-income country: Can they be sustained?

PONE-D-19-24025R3

Dear Dr. Murni,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Surbhi Leekha

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

4 Jun 2020

PONE-D-19-24025R3

Multifaceted interventions for healthcare-associated infections and rational use of antibiotics in a low-to-middle-income country: Can they be sustained?

Dear Dr. Murni:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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on behalf of

Dr. Surbhi Leekha

Academic Editor

PLOS ONE