A national survey of antibacterial consumption in Sri Lanka.

INTRODUCTION: Optimizing the use of antibacterial medicines is an accepted strategy to combat the antibacterial resistance. Availability of reliable antibacterial consumption (ABC) data is a prerequisite to implement this strategy.
OBJECTIVES: To quantify and describe the national ABC in Sri Lanka and to examine any differences in the consumption between public and private sector.
METHODS: The methodology for this survey was adapted from World Health Organization (WHO) methodology for a global programme on surveillance of antimicrobial consumption. Aggregate data on national consumption of systemic antibacterials (J01- Anatomical Therapeutic Chemical Classification (ATC) for 2017 were retrospectively extracted from all available data sources and classified using ATC classification. Quantity of consumption was converted to Defined Daily Doses (DDDs). Data are presented as total consumption and comparison between the public and private sector. Selected key quality indicators of ABC were compared between these two sectors.
FINDINGS: From the available data sources, the total ABC in 2017 was 343.46 million DDDs. Private sector consumption accounted for 246.76 million DDDs compared to 97.96 million DDDs distributed to entire public sector by the Ministry of Health. Beta-lactam-penicillins antibacterial group accounted for 58.79% in public sector compared to 27.48% in private sector while macrolides, quinolones and other beta-lactam antibacterials accounted for 60.51% in the private compared to 28.41% in public sector. Consumption of Reserve group antibacterials was negligible, and limited to private sector. Watch category antibacterials accounted for 46%, 24% and 54% of the total, public and private sector consumption, respectively.
CONCLUSIONS: A disproportionately higher use of broad spectrum and Watch category antibacterials was observed in the private sector which needs further study. This national consumption survey highlights the need and provides the opening for establishment of ABC surveillance in Sri Lanka.

Introduction

Antimicrobial resistance (AMR) is a major public health challenge [1]. A global survey conducted by the World Health Organization (WHO) in 2014 has shown a high level of resistance to both first line and Reserve category antibacterials for nine pathogenic bacteria responsible for common infections in all WHO regions [2]. Infection with such resistant microorganisms result in longer illnesses, increased mortality, prolonged hospital stays and increased overall costs [1, 3, 4]. Antimicrobial resistance affects all areas of health including veterinary and environmental practices and impacts the entire society and its economy [2, 5].

Principally driven by low-and-middle-income countries (LMICs) the global antibacterial consumption (ABC), expressed in defined daily doses (DDD), has increased by 65% from 2000 to 2015 [6]. An increased use of broad-spectrum and last-resort antibacterials was observed in both LMICs and high-income countries (HICs) during this period [6]. If the present policies continue, ABC is expected to increase by 200% in 2030 compared to the consumption in 2015 [6].

The association between ABC and development of antibacterial resistance (ABR) is well documented and a reduction of inappropriate use of antibacterials could reduce development of resistance [7, 8]. Countering ABR needs long term strategies which include strengthening the healthcare systems and enacting regulations to ensure appropriate use of and access to antibacterial agents [5]. To enhance access to antibacterials for treatment of commonly occurring infections and their appropriate use, the WHO introduced the Access, Watch, and Reserve (AWaRe) classification of antibacterials as part of Essential Medicines List [9]. With the application of AWaRe classification, the WHO national level target is that 60% of the antibacterials used should be from the Access category by 2023 [9].

The WHO’s Global Action Plan (GAP) for Antimicrobial Resistance (AMR) [5] calls for member states to put in place national plans to urgently combat AMR. Five strategic objectives have been identified to achieve the goals of the GAP [5]. The fourth objective viz to “Optimize the use of antimicrobial medicines in human and animal health” needs reliable antimicrobial consumption (AMC) data [5, 10]. Data on AMC are vital to understand AMR, as selection pressure due to use of antimicrobials is a preventable driver for development and spread of AMR [7, 8]. While data on AMC are collected and analysed in many high- and middle-income countries, there is limited data on AMC from lower-income countries [10]. However, the available data from LMICs show a greater increase in the use of Watch category antibacterials and a greater reduction in the Access to Watch ratio [6, 11] To effectively curtail AMR, surveillance data from AMR must be linked to that of AMC [12].

The WHO methodology for a global programme on surveillance of antimicrobial consumption provides a practical framework to obtain such data in resource limited countries (RLC) [13]. This involves the collection of “Consumption” and “Use” data and recommends that countries separate “consumption data” from “use data” as the objectives, methods and outcomes for these two categories of data are different. “Consumption data” refers to estimates derived from of aggregated data, mainly derived from import, sales or reimbursement databases whereas “use data” refers to estimates derived from patient-level [13].

Sri Lanka is a lower middle-income country [14]. Both the public and the private sectors provide allopathic healthcare services in Sri Lanka but the share of care is different for inpatients and outpatients. The public sector provides the bulk of inpatient care while outpatient care is shared between both public and private sectors [15]. Infections are a leading cause of morbidity and mortality in the public sector health care institutions with zoonotic and other bacterial infections being the 2nd leading cause of death in 2017 with the highest case fatality rates seen from septicaemia and pneumonia [15]. A similar picture was seen in children where pneumonia and other bacterial infections were the 4th and 5th leading causes of death [15]. The absence of morbidity and mortality data from the private sector makes comparisons between the sectors difficult.

The country imports the bulk of its antimicrobials through the State Pharamceuticals Corporation (SPC), which is the State’s procurement arm, and independent private importers. Limited amounts of antimicrobials are manufactured by the State Pharmaceutical Manufacturing Corporation (SPMC) and individual local manufacturers. The SPC is the sole supplier of antimicrobials to the public sector. It directly imports and also procures from local manufaturers and are distributed to medical institutions in the public sector by the Medical Supplies Division (MSD) of the Ministry of Health. When antibacterials are not available at the MSD, the individual hospitals have the option to procure them from retail pharmacies as “local purchases”. Antibacterials for the healthcare institutions in the private sector are purchased from SPC, independent private importers and local manufacturers.

Sri Lanka has an established and successful AMR surveillance programme, coordinated by the Sri Lanka College of Microbiologists, but there is no system in place to obtain aggregated AMC data. The available AMR data shows significant resistance by bacteria causing common infections to 1st line antibacterials [16-18]. Available AMC data from Sri Lanka are either limited to pharmaceutical sales data which lacks information of the public sector ABC [6, 19] or only from the public sector and lacks information about consumption in the private sector [20]. The public sector data showed an increase of ABC by 143% (44.4–108.2 million DDDs) with a significant shift towards the use of broad-spectrum antibacterials from 1998 to 2018 [20]. There is, however, no system at present to correlate AMC/ABC data with AMR/ABR patterns in the country.

The Sri Lanka Association of Clinical Pharmacology and Therapeutics (SLACPT), in collaboration the National Focal Point for combating AMR in Sri Lanka, therefore conducted this national survey of antibacterial consumption for 2017. Although the WHO methodology [13] has defined a core set of antimicrobials namely antibacterials, antibacterials for alimentary tract and nitroimidazole derivatives for protozoal diseases that all countries should monitor in their surveillance programme, this study has surveyed only the antibacterial consumption (ABC).

Our objective was to quantify and describe the national antibacterial consumption in Sri Lanka and compare the consumption between public and private healthcare sectors. This paper presents the methods adopted, discusses the key findings and the problems encountered when conducting the survey. Our findings would be helpful when planning for comprehensive national ABC/AMC surveys or surveillances.

Materials and methods

Study design and data sources

The methodology of this study was adapted from WHO methodology for a global programme on surveillance of antimicrobial consumption [13]. It was a descriptive cross-sectional study in which aggregate data on antibacterial consumption in 2017 were retrospectively extracted from all available data sources in 2018. The WHO methodology recommends to survey antimicrobials including anti-protozoals, anti-fungals, anti-malarials and anti-virals in addition to antibacterial agents (ABAs). However, to start with, we have surveyed only the ABAs listed under antibacterials for systemic use (J01) in the Anatomical Therapeutic Chemical (ATC) classification system [21].

Local manufacturing of antibacterials is limited in Sri Lanka and the importers are the major supplier of antibacterials for the country. State Pharmaceuticals Corporation is the sole importer for public sector and Rajya Osusala Pharmacies (retail pharmacy chain of SPC). It also imports for private market. In addition, there are many importers who cater for private market. Considering the supply system in Sri Lanka, we approached the Sri Lanka Customs, Department of Imports and Exports, SPC, State Pharmaceutical Manufacturing Corporation (SPMC), Medical Supplies Division (MSD), private importers and the private manufacturers (list was obtained from the NMRA website, www.nmra.gov.lk accessed on 31st August 2018) for ABC data. As these data sources are expected to provide the data for the entire country, no sampling was done. Details of all antibacterials were requested irrespective of their essential medicine list or Sri Lankan Formulary listing status. We provided the ATC code (J01) for those who had the data in the ATC format and a list containing the names of antibacterials categorized under J01 for those who did not have the data in the ATC format. A custom-made MS Excel worksheet was developed based on WHO methodology and our previous experience in ABC surveillance in Colombo district [22]. Data from the MSD were electronically transferred. All other data sources submitted data in paper format and these were manually entered into the Excel worksheet. All the precautions were taken to ensure the accuracy of data entry. The WHO methodology recommends a detailed product-level electronic data to be collected for ABC surveillance programmes. However, for this survey, data which had the minimum details, name, dosage form, strength and quantity were considered as “complete” and included for analysis.

Measures of antibacterial consumption

The WHO defines consumption data as “estimates derived from aggregated data sources such as import or wholesaler data, or aggregated health insurance data where there is no information available on the patients who are receiving the medicines or why they are being used” [13]. National antibacterial consumption (ABC) data provide a proxy estimate of use of these agents in the country. Antibacterials for systemic use (J01, ATC classification level 2) obtained from the data sources were further classified to level 3, 4 and 5. We have presented the consumption data at level 3 (therapeutic or pharmacological sub-group) and level 5 (chemical substance). Quantity of consumption is expressed as Defined Daily Doses (DDDs) using the formula given below. The DDD is defined as “the assumed average maintenance dose per day for a medicine used for its main indication in adults”. Total grams consumed was determined by summing the amounts of active ingredient across the various formulations (different strengths of tablets or capsules, syrup formulations) and pack sizes. The DDD value is assigned by the WHO Collaborating Centre and obtained from their website (http://www.whocc.no/atc_ddd_index/). Number of DDDs consumed was calculated by dividing the total consumption (in grams) by DDDs (in grams). Though the WHO methodology recommends that the variables for consumption estimates should include packages and DDDs, we have used only DDDs as package details were not available for this retrospective survey. In addition to presenting the total consumption data obtained from different data sources, we have also compared the public sector data with that of private sector, keeping in mind that the private sector data could be an underestimate as it was impossible to verify the accuracy and completeness of data. The supply chain of antibacterials for public and private sectors in Sri Lanka is shown in Fig 1 which shows that the chances of duplication of data is minimal. We also have compared few key ESAC based quality indicators [23] of ABC as well as the volumes of antibacterials in the “Access, Watch and Reserve” categories (AWaRe classification) between these two sectors [9].

Fig 1

Antibacterial supply chain in Sri Lanka.

Ethical considerations

Ethics Review Committee of Sri Lanka Medical Association exempted this survey from review (ERC/18/14). A formal letter of request with a copy of ethics review committee’s letter of exemption was sent to all the institutions who had the data. Investigators personally visited many of these institutions to explain the aim of survey. Data presented here are from the consenting institutions. Data comprised aggregate data of the amount of antibacterials distributed, imported or manufactured by these institutions and not individual patient or hospital data.

Results and discussion

We analyzed the data from the MSD, SPC, one local manufacturer (SPMC) and 12 private importers. Four local manufacturers did not provide data. Although 78 are registered as private importers with the NMRA, the exact number of companies that actually imported antibacterials in 2017 was not available. The rough estimate from the NMRA records was 40 and 12 of them provided analyzable data. Four out of the 5 leading importers provided analyzable data whilst data provided by one major importer had to be discarded as the Company did not provide the information on strengths of the dosage forms which is essential to calculate DDD. The MSD data is reliable and is the almost complete data for public sector. The SPC provided data separately for public and private sector while SPMC provided cumulative data for both sectors. Data provided by the private importers is their imports for private sector. The SPC data for private sector may include the data from companies that have not provided their imports data to us (Fig 1).

The total volume of antibacterial agents (ABA) (in million DDDs) imported/distributed in 2017 by the respective agencies is shown in Table 1.

Table 1

Total volume of ABAs (in million DDDs) imported/distributed in 2017 by the different agencies.

Agency	Volume of ABAs (in million DDDs)
1. Distributed by SPC to private sector	163.04
2. Distributed by MSD to public sector	97.96
3. Distributed by SPMC to both to public and private sector	61.18
4. Imported by private sector	59.30
5. Manufactured by SPMC	56.08
6. Distributed by SPC to MSD	31.43
7. Distributed by SPC to its retail pharmacies (Rajya Osusala)	24.41

In Sri Lanka, most of the inpatient care is provided by the public sector while the outpatient care is shared between the public and private sectors [15]. Despite bulk of patient care being provided by the public sector, the ABC in the private sector (Table 1; data sources 1, 4 and 7) was 246.76 million DDDs compared to 97.96 million DDDs distributed to the public sector by the MSD, which is the sole supplier of medicines to the public sector (data source 2).

The SPC was initially established as a procurement agency for the public sector. However, in 2017 a significant 74.5% of its antibacterial imports were to the private sector (163 million DDDs,) while only 14.35% was to the public sector (31.43 million DDDs). The amount distributed to the public sector by MSD includes leftover stocks from 2016 and hence more than what it had received from the SPC in 2017.

The higher ABC of private sector could be due to the significant proportion of outpatient care that is provided by the private sector which includes the private hospitals and independent family physicians in the community. The antibacterials prescribed by these sectors are obtained from the retail pharmacies in the private hospitals and in the community and will contribute towards the increased ABC of the private sector.

Comparison of ABC between public and private sectors

As Sri Lanka has a free public health care system and a fee levying private health care system, we analyzed the data according to the total ABC and in the two sectors. The top four groups of antibacterials consumed in Sri Lanka were beta-lactams, penicillins, other beta-lactams, macrolides and quinolones (Table 2). However, major differences were observed in the proportion of volumes consumed with these categories between the public and private sectors. The beta-lactam antibacterials, penicillins considerably outnumbered (58.57%) the other three groups (13.7%, 7.8%, and 6.8%) in the public sector whereas each of the top four groups accounted for between 15–36% of the ABC in the private sector. Compared to the public sector, the consumption of macrolides, quinolones and other beta lactam antibacterials is disproportionately higher in the private sector.

Table 2

Consumption of different pharmacological sub-groups of antibacterials in the country and public and private sectors.

ATC code	ATC level 3 classification of ABAs	ABA consumption volume in DDD per million							DDD per 1000s population
		Public sector (%)		Private sector (%)		Total (%)
J01A	Tetracycline’s	5.94	(6.06)	14.89	0.01	20.83		(6.04)	0.98
J01B	Amphenicols	0.00	(0.00)	0.19	5.90	0.19		(0.06)	0.01
J01C	Beta-lactam antibacterials, penicillins	57.38	(58.57)	67.80	2.62	125.18		(36.31)	5.90
J01D	Other Beta-lactam antibacterials	13.38	(13.66)	42.20	0.10	55.58		(16.12)	2.62
J01E	Sulfonamides and trimethoprim	0.50	(0.51)	1.71	3.22	2.21		(0.64)	0.10
J01F	Macrolide, lincosamide and streptogramins	7.69	(7.78)	60.57	0.01	68.26		(19.80)	3.22
J01G	Aminoglycoside antibacterials	0.14	(0.14)	0.00	2.51	0.14		(0.04)	0.01
J01M	Quinolone antibacterials	6.66	(6.82)	46.57	0.90	53.23		(15.44)	2.51
J01X	Other antibacterials	6.28	(6.41)	12.84	16.26	19.12		(5.55)	0.90
	Total	97.96	100.00	246.76	0.98	344.72	100.00		16.26

The consumption of most frequently consumed antibacterials (5th and last level of ATC classification) within these top four groups are shown in Table 3. (S1 Table). Substantial differences were observed between public and private sectors in the consumption of individual antibacterials within each of the top four groups. In the private sector co-amoxiclav was the most consumed antibacterial in J01C group and azithromycin in the J01F group while amoxicillin and erythromycin were the equivalents in the public sector. Interestingly, benzyl penicillin was consumed only in the public sector.

Table 3

Most consumed antibacterials of the top four pharmacological groups in private and public sectors.

ATC level 5 classification of ABAs (Code) under each level 3 classification	Name of classes and individual ABAs	Public sector (%)		Private sector (%)
		DDDs	(%)	DDDs	(%)
J01C	Beta-lactam antibacterials, Penicillins
J01CA04	Amoxicillin	21.91	(22.37)	22.66	(9.18)
J01CE01	Benzyl penicillin	16.95	(17.30)	-	-
J01CF02	Cloxacillin	7.96	(8.13)	2.49	(1.01)
J01CF05	Flucloxacillin	0.32	(0.33)	1.93	(0.78)
J01CR02	Co-Amoxiclav	8.72	(8.90)	39.07	(15.83)
J01D	Other Beta-lactam antibacterials
J01DB01	Cephalexin	4.57	(4.67)	16.12	(6.53)
J01DC02	Cefuroxime	7.79	(7.95)	20.91	(8.47)
J01DD08	Cefixime	0.05	(0.05)	4.59	(1.86)
J01F	Macrolide, Lincosamide and Streptogramins
J01FA01	Erythromycin Stearate	3.52	(3.59	6.13	(2.49)
J01FA09	Clarithromycin	2.67	(2.73)	13.58	(5.50)
J01FA10	Azithromycin	1.26	(1.29)	38.74	(15.70)
J01M	Quinolone antibacterials
J01MA01	Ofloxacin	0.03	(0.03)	0.32	(0.13)
J01MA02	Ciprofloxacin	5.81	(5.93)	34.93	(14.16)
J01MA06	Norfloxacin	0.52	(0.53)	2.76	(1.12)
J01MA12	Levofloxacin	0.22	(0.22)	8.05	(3.26)

Quality indicators of ABC for the country as a whole and separately for public and private sectors are given in Table 4. Indicators are calculated for total data to show how one sector affects the country data.

Table 4

Comparison of few key quality indicators of ABC between public and private sector.

	Indicator	Public sector	Private sector	Total
J01CE_%	Consumption of β-lactamase sensitive penicillins (J01CE) expressed as percentage of the total consumption of antibacterials for systemic use (J01)	18.77	0.18	5.46
J01CR_%	Consumption of combination of penicillins, including β -lactamase inhibitor (J01CR) expressed as percentage of the total consumption of antibacterials for systemic use (J01)	8.98	15.83	13.89
J01DD+DE_%	Consumption of third and fourth generation of cephalosporins (J01(DD+DE)) expressed as percentage of the total consumption of antibacterials for systemic use (J01)
	1st Generation	4.67	6.55	6.01
	2nd Generation	7.95	8.52	8.35
	3rd Generation	0.72	1.98	1.62
	4th Generation	0.00	0.00	0.00
J01MA_%	Consumption of flouroquinolones (J01MA) expressed as percentage of the total consumption of antibacterials for systemic use (J01)	6.71	18.81	15.31
J01_B/N	Ratio of the consumption of broad (J01(CR+DC+DD+(F-FA01))) to the consumption of narrow spectrum penicillins, cephalosporins and macrolides (J01(CE+DB+FA01))	0.81	5.25	2.86

Antibacterials consumption according to WHO AWaRe Classification

Fig 2 shows the consumption of antibacterials in the “Access, Watch and Reserve” categories for the country as a whole and separately for public and private sector (S2 Table).

Fig 2

Consumption of antibacterials in Access, Watch and Reserve categories.

Of the total antibacterials consumed, 54.19% were from the Access category while 45.57% were from the Watch group with an Access: Watch ratio of 1.18. However, in the public sector this ratio was 3.16 while it was 0.84 in the private sector.

The single most important difference observed between public and private sector (Tables 2–4, Fig 1) was disproportionately higher use of broad spectrum antibacterials in the private sector. We compared the top ten oral and parental antibacterials used between the sectors (Tables 5 and 6).

Table 5

Comparison of the top ten oral antibacterials consumed between sectors.

Public sector				Private Sector
ABM	AWaRe group	DDDs in million	%	ABM	AWaRe group	DDDs in million	%
Amoxicillin	A	21.91	28.96	Co-Amoxiclav	A	38.95	15.89
Cloxacillin	A	7.82	10.33	Azithromycin	W	38.74	15.81
Cefuroxime	W	6.7	8.86	Ciprofloxacin	W	34.91	14.25
Co-Amoxiclav	A	6.2	8.2	Amoxicillin	A	22.66	9.25
Doxycycline	A	5.94	7.85	Cefuroxime	W	20.7	8.45
Ciprofloxacin	W	5.81	7.68	Cephalexin	A	16.12	6.58
Metronidazole	A	4.62	6.11	Doxycycline	A	14.35	5.86
Cephalexin	A	4.57	6.04	Clarithromycin	W	13.49	5.5
Erythromycin	W	3.52	4.66	Metronidazole	A	12.03	4.91
Clarithromycin	W	2.62	3.47	Levofloxacin	W	8.03	3.28

Table 6

Comparison of the top ten parental antibacterials consumed between sectors.

Public sector				Private sector
ABM	AWaRe group	DDDs in million	%	ABM	AWaRe group	DDDs in million	%
Benzyl penicillin	A	16.95	75.98	Flucloxacillin	A	0.35	20.57
Co-amoxiclav	A	2.52	11.29	Ampicillin	A	0.24	14.43
Cefuroxime	W	1.08	4.86	Ceftriaxone	W	0.23	13.53
Ceftriaxone	W	0.48	2.16	Cefuroxime	W	0.21	12.39
Meropenem	W	0.3	1.35	Metronidazole	A	0.14	8.53
Cefotaxime	W	0.14	0.64	Meropenem	W	0.12	7.26
Cloxacillin	A	0.14	0.62	Co-amoxiclav	A	0.12	6.92
Flucloxacillin	A	0.13	0.56	Clarithromycin	W	0.09	5.32
Gentamicin	A	0.11	0.48	Moxifloxacin	W	0.04	2.27
Levofloxacin	W	0.09	0.38	Cefotaxime	W	0.03	1.96

While both sectors have consumed large amounts of oral and parenteral antibacterials in the Watch category, this is much more in the private sector. Notable is the disparity in the consumption of ceftriaxone, cefuroxime and meropenem. This is a concern as it would contribute significantly towards the spread of antibacterial resistant bacteria in the country, Surveillance data on both resistance and consumption are essential to obtain a comprehensive picture of antibacterial resistance. Correlating ABC data with the ABR patterns will help to identify areas that need further action. While national data on ABR patterns are available in Sri Lanka [24, 25], to the best of our knowledge this is the first attempt at obtaining national antibacterial consumption data. Previous data from Sri Lanka which have been included in other surveys [6, 19, 20] have been obtained from either only pharmaceutical sales [6, 19] data or only public sector ABC data [20]. Adopting WHOs’ standard methodology made it possible for us to compare our findings with similar studies done globally and in the region.

We compared Sri Lanka’s ABC in 2017 with global surveys on ABC [6, 11] and that of the ESAC-Net countries [26]. In 2015, the most commonly consumed antibacterial classes globally were broad-spectrum penicillins (J01CA), cephalosporins (J01D), quinolones (J01M) and macrolides (J01F) [6, 11]. This was similar to the top four groups of antibacterials consumed in Sri Lanka. The average total ABC for systemic use (ATC group J01) in the EU/EEA (23.4 DID) [26] was much higher than that of Sri Lanka for 2017 (16.26 DID). A key finding was the ratio of the consumption of broad spectrum to narrow spectrum penicillins, cephalosporins and macrolides (J01_B/N). This was 2.86 for the country, 0.81 for the public sector but a significant 5.25 for the private sector (Table 4). This ratio is higher than what was seen in the community consumption for ESAC-Net countries i.e. 2.25 [26]. The higher DID and the comparatively lower J01-B/N in ESAC-Net countries could be due to greater access to and better regulation of antimicrobials in these countries.

Direct comparison with other WHO South East Asian Region (SEAR) countries in the region was limited by the lack of studies and the disparity of data sources in different studies. Although South East Asian Region (SEAR) was excluded in the WHO report on surveillance of antibacterial consumption from 2016–2018 due to the lack of data, a high level of consumption of cephalosporins and quinolones was found in some countries of the region [2]. A higher consumption of other beta-lactam antibacterials, macrolides and quinolones was seen in the private sector compared to that of the public sector of Sri Lanka. This was somewhat similar to that of the retail private sector in India which also showed an increase in the use of 3rd generation cephalosporins, penicillins with beta-lactamase inhibitors, and of newer classes of antibacterials like carbapenems, lincosamides and glycopeptides [27].

As the WHO recommends that the Watch group should be prioritized as key targets of stewardship programs and monitoring as they have higher resistance potential [9], we analysed the data according to WHO’s AWaRe classification (9). Despite a 54.19% overall use of Watch antibacterials in the country, a higher consumption of these antibacterials was seen in the private sector (54.11%) compared to the public sector (24.11%) (Fig 2).This may be an under representation of the consumption of Watch antibacterials in both sectors as local purchase by public sector hospitals and direct purchase from importers by private sector hospitals and retail pharmacies have not been completely captured in our data especially as we had to discard data from a major importer. The disparity could be still higher as we do not have complete data from the private sector imports. A similar pattern where more antibacterials in the Watch group are consumed is also seen in several European countries and Japan [10] and in India [16, 28]. The higher consumption of Watch group antibacterials in the private sector in Sri Lanka is a concern especially as there is no data to suggest that the causative bacteria and/or their antibacterial sensitivity patterns differ between the sectors. This is more alarming as there is an increasing emergence of multi drug resistant bacteria in the country [16–18, 29]. It has also been shown that some of the pathogens causing lower respiratory tract infections are resistant to the first line Access antibacterials but show an increased sensitivity to 2nd line (Watch) agents [30]. Infections with these resistant bacteria to first line antibacterials would add a significant burden to the health budget.

A significant finding from our survey is the disproportionately higher use of broad-spectrum antibacterials in the private sector when compared to the ABC of the public sector. The disparity is difficult to explain, especially as prescribers in both these sectors being largely the same. In addition, the National Antibacterial Guidelines for empirical treatment of infections [31] have been widely disseminated to the prescribers and they are expected to adhere to these irrespective of the place of practice. A major factor that affects antibacterial consumption in the public hospitals in Sri Lanka is the highly limited hospital formulary available to prescribers. The formulary is based on the country’s EMLs and the medicines are made available strictly according to it to the public sector institutions. Even though prescribers have the facility to “local purchase” medicines, this does not give them the same availability of medicines as those practicing in the private sector as the patients who seek care from these institutions are largely from lower income segments of the society. The freedom to prescribe any medicine that is available in the country and improved financial status of the patients who seek treatment from the private sector could contribute to the greater use of broad-spectrum and newer antibacterials in the private sector.

However, inappropriate prescriptions of antibacterials are seen in the outpatient management of respiratory infections in the public sector hospitals too [32, 33]. Patients demand for antibacterials as a “quick fix” for infections, incorrect physician perception of the need for antibacterials, fear of bacterial super infection in viral diseases and the high patient volume seen in outpatient settings limiting the time for assessment have led to a greater prescription of broad spectrum antibacterials [33].

The Government of Sri Lanka has initiated many regulatory mechanisms to curtail inappropriate antibacterial use. All antibacterials are registered under Schedule 11B by the National Medicines Regulatory Authority and are prescription only [34]. Despite such regulations it is still possible to obtain antibacterials from retail pharmacies without a valid prescription [35, 36]. Self-medication of antibacterials by patients [36] and the freedom to access any practitioner without an appropriate referral which could lead to duplication and/or inappropriate prescriptions, also contribute to an increase in ABC and AMR in the country.

While we do not have complete national data, this paper presents the maximum possible extractable data on ABC in Sri Lanka for the year 2017. As recommended by the WHO for counties which are starting antimicrobial surveillance, we have used procurement/issues data available at the central. This, however, does not reflect what is actually consumed by the end user. The key strength of our study is usage of standardized WHO methodology for reporting ABC in DDD and using ATC classification. The DDD methodology allowed us to use aggregated antibacterial purchase data and made it possible to compare our data with regional and global data. However, the DDD may not reflect the prescribed daily dose (PDD) for individual patients and cannot be used to measure consumption in paediatric wards since the measure is based on adult dosing [37]. It also does not accurately measure antibacterial consumption in cases of renal or hepatic dysfunction, often underestimating the actual antibacterial usage [37].

An important limitation of our study was the inability to capture all national data. This was largely due to incomplete and inadequate record keeping by the Customs and private importers. The inability of the SPMC to provide consumption data based on the sector to which it supplied added to the incomplete national consumption data. For meaningful interpretation of data, the total numbers of DDDs derived as consumption estimates should be adjusted for the population to which the data apply. Despite these limitations we have adjusted for the population (DID) to compare with similar studies as there is no separate DDD for children [21]. Therefore, we had to use the DDDs for adults in the calculations although both adults and children would have consumed the antibacterials.

This is the first time an attempt has been made to document the national consumption of antibacterials in Sri Lanka. While there are some limitations and the actual consumption could be an under estimation, we are confident that the pattern of antibacterial consumption documented in this paper is unlikely to change even if we have all the data on antibacterial consumption. The generalizability of our findings would depend on the systems in place to regulate and survey antibacterial consumption. The paper highlights the need for better regulation of antibacterial consumption and the need for robust surveillance systems. The latter could be both labour and resource intense to LMICs like Sri Lanka.

Conclusions

Despite limitations our study provides the first national ABC data from Sri Lanka which captures the use in both public and private sectors. Although limited to the health care sector, it highlights the problems a LMIC face when trying to apply globally accepted survey methods to evaluate aspects of ABC. Establishing a central unit to coordinate all activities related to both AMR and AMC, using accepted classification when coding imports, getting the private sector into the programme and creating a central data base which records, analyses and generates statistics routinely are key areas that need attention for better surveillance of antimicrobial use. As antibacterials use is to some extent patient and prescription driven in Sri Lanka, education campaigns targeting both patients and prescribers are needed to change behaviours and prescribing habits. Better implementation of existing regulation is vital to curtail antibacterial misuse.

Recommendations for policy makers

We strongly recommend the establishment of robust and sustainable surveillance systems to periodically survey and monitor antibacterial consumption. A central body to coordinate the activities of antibacterial consumption is crucial. Surveillance systems should be developed, and adequate funding and resources to collect and analyze data should be made available. All data should be coded at the point of entry using the ATC classification which would help in analysis of data and to compare the consumption trends with other countries.

The data on ABC should be linked with that of ABR to identify trends of antibacterial use and changes in antibacterial sensitivity patterns. The ABC should be reviewed annually to identify trends of use and to regularize antibacterial consumption. Based on the surveillance data, national policies and guidelines for antibacterial use should be developed and measures should be in place to ensure that they are adhered to. Linking up with the WHO programme that has been introduced for LMICs [38] is important to compare the country’s activities with others.

Comparing the volume of antibacterial consumption (ATC classification Level 5) between private and public sector.

(DOCX)

Click here for additional data file.

AWaRe categorization of all the antibacterials.

(DOCX)

Click here for additional data file.

17 May 2021

PONE-D-21-11873

National surveillance of antibacterial consumption in Sri Lanka

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Reviewer #1: The manuscript addresses a timely topic which is very important for all the developing countries. It also stresses the possibility of antibiotic abuse (especially second line antibiotics) within the private sector which can be controlled with appropriate measures as discussed in the article. It is well written except for a few changes as per my comments. Statistically, they have only used percentages which is descriptive enough given the content of the article. Please delete the words that were highlighted in the Introduction and add the comment I stressed to the discussion.

Reviewer #2: The manuscript entitled “National surveillance of antibacterial consumption in Sri Lanka” is a descriptive study aimed to quantify and describe national antimicrobial consumption. It is very important concept and has practical policy implications; however, authors need to address the following major comments/suggestions to improve the quality of the paper before it will come to publication.

General comment

The manuscript needs to be reformatted by referring the journal style, excessive bolding of words and excessive unnecessary abbreviations should be reduced, and appropriate citations, repeated editing and proof reading are required. In addition to making the paper mind-numbing, those things are very technical and reduce the readability of the paper, and hence, it needs careful revisions.

Detail comments/sugessions

Title

• I suggest the title need to be revised. I think it is a cross sectional study, which is a survey, but the title saying surveillance. Unlike your study, surveillance is an ongoing collection of information to detect changes or it is repeated survey.

Abstract

• The abstract lacks background.

• The word WHO, in method section need to be written in full. You should first write the full term before you abbreviated. Full term do not need to be in caps and brackets, just abbreviations. Similarly for ABC in the finding section of abstract.

• The sentence “Reserve and watch category antibacterials accounted for 46, 24 and 54% of the total, public and private sector consumption” not clear and needs revisions.

• The aim of the study and the conclusion is mismatched. The aim is to describe and quantify, but the conclusion seems comparisons between public and private. The recommendation “Our study has provided the evidence that antibacterial surveillance is possible in resource limited countries and it must be made mandatory” needs revisions. Because, the recommendation is beyond the scope of the study, recommended to other resource limited countries are no appropriate, as the method including sampling procedure used in the study are not allowed to infer to other countries. I also suggest to not use the word mandatory since recommendation are not approached as obligatory.

• I not saw key words. Please add.

• The background, objective, method, results and conclusions of manuscript need to be reformatted including make them bold.

Background

• Revise the typo error (two point after the title) of “Introduction:”

• The paper generally needs serious citation revisions. For example, in the first paragraph only, from five sites that need citations, only one has citation and the rest four are not. Please, also add more evidences/citations for those cited also.

• The third paragraph of introduction also missed citations and needs revised again.

• The last paragraph of introduction “therefore conducted a national surveillance of antibacterial consumption (ABC)” needs revisions. As suggested above to the title, this study is not surveillance rather a survey. The two concepts are quite different. What are the significance of the sentence “This paper outlines the methods adopted, key findings and recommendations for establishment of a national surveillance programme”.

• The background section lacks and needs to revise based on updated prior literatures on global, regional and national picture about the antimicrobial consumption.

• Authors also need to add contribution of this study and practical policy implication.

• I couldn’t see the aim/s and or objective of the study in this section that is mentioned in the abstract, authors need to expand those points including the rationale of the study.

Methods

• There are many bolded disorganized subsections. No need to say background here. Please reformat them based on the journal style. For instance, study design, data source and sampling procedure in to one subsection. Variables of the study (outcome variable vs explanatory variables, including their definitions with appropriate citations, coding and categories in another subsection. Then, data entry, data analysis, and presentation of results as statistical analysis, the ethical issues in another subsection like that. Please elaborate a little more on the ethical issues. The ethical issues mentioned in the data source section need to be bring in to ethical consideration section.

• Please summarize data source and availability of data into one.

• Authors mentioned as it indicates the 2017 national antimicrobial consumption. However, the data collection period or this specific study is not mentioned.

• I couldn’t found about sampling technique and procedures use in the study. Who were the source and sampled population? How they were selected? Who were the data collectors? What are the tools?

Results

• The results need to be summarized with subsection to make clearer of the key findings.

• Please avoid the typo error (colon after the title of results).

Discussion

• The discussion is poor. It seems redundancy with results, and therefore, needs careful revisions; compare and contrast of your key findings with prior literatures and justify or discuss in details especially for inconsistency findings. It also have citations problem.

Conclusions

The conclusion is not specific and not aligned with the findings. Please first write the word in full before you abbreviated it such as LMICs. You recommend to LMICS, but I couldn’t see any evidence in the method sections including sampling technique, that support for generalizability of the findings for LMICs. The conclusion is beyond the study’s scope and not specific. Please revise it.

Reviewer #3: This is a comprehensive study looking at antibiotic consumption patterns in a LMIC. It is well-written except for a few grammatical errors (Introduction - line 3, page 5 - line 10, page 20 - lines 1 and 6). Data however is far from complete since many potential sources have not been able to provide usable data (ie only 12/78 private importers have submitted usable data).

A major factor that affects antibiotic consumption in the public hospitals in Sri Lanka is the highly limited formulary that is available for prescribers, compared to the private sector. This fact has not been taken in to account in the Discussion. Being able to 'locally purchase' antibiotics in the public sector does not equate to the choice of antibiotics available in the private sector.

No information on antibiotic resistance patterns in the country is provided. Therefore, the usefulness and applicability of the prescription patterns is not explored in detail.

**********

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Reviewer #1: Yes: Dr Chanika Alahakoon (MBBS, MPhil), Department of Physiology, Faculty of Medicine, University of Peradeniya, Sri Lanka

Reviewer #2: Yes: Betregiorgis Zegeye

Reviewer #3: No

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Submitted filename: PONE-D-21-11873_reviewer.pdf

Click here for additional data file.

10 Jun 2021

PONE-D-21-11873

National surveillance of antibacterial consumption in Sri Lanka

Amended title: A National survey of antibacterial consumption in Sri Lanka

Response to Reviewers

COMMENTS RESPONSE FROM AUTHORS

ACADEMIC EDITOR

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

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https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Thank you very much

We apologize for not following the journal style

We have now revised the whole manuscript based on the journal style guide for title page, main body, tables, figure and references

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.

If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. Thank you

This is a retrospective study of medicine supplies/imports data

Ethics Review Committee of Sri Lanka Medical Association exempted this survey from ethics review committee approval (ERC-18/14). Formal request letter with a copy of ethics review committee approval was sent to all the institutions who had the data. Investigators personally visited many of these institutions to explain the aim of survey. Data presented here are from the consenting institutions. Data comprised aggregate data of amount of antibacterials distributed, imported or manufactured by these institutions and not individual patient or hospital data.

We have stated this under ethical considerations in the methods section

We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions

Please see below (cover letter comment)

Cover letter

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

The data underlying this study belong to many third parties, Ministry of Health, State Pharmaceutical Corporation, State Pharmaceutical Manufacturing Corporation and private Pharmaceutical Companies. Raw data used to analyse antibiotic consumption in this manuscript is either state owned or private company/industry owned. Data were given to us under the agreement that the raw data will not be shared. Hence, we are unable to provide raw data in public domain. We confirm that we did not have any special access to the data that other researchers would not have.

REVIEWER 1

The manuscript addresses a timely topic which is very important for all the developing countries. It also stresses the possibility of antibiotic abuse (especially second line antibiotics) within the private sector which can be controlled with appropriate measures as discussed in the article. It is well written except for a few changes as per my comments. Statistically, they have only used percentages which is descriptive enough given the content of the article. Please delete the words that were highlighted in the Introduction and add the comment I stressed to the discussion. Thank you very much. The typo has been deleted.

Add another limitation. The fact that you calculated the doses assuming only adults uses the antibiotics

Thank you for this. We have added this limitation and appropriate reference has been cited.

Grammatical and typo errors Thank you and have been corrected

REVIEWER 2

General comments

The manuscript needs to be reformatted by referring the journal style, excessive bolding of words and excessive unnecessary abbreviations should be reduced, and appropriate citations, repeated editing and proof reading are required. In addition to making the paper mind-numbing, those things are very technical and reduce the readability of the paper, and hence, it needs careful revisions. Thank you very much for the comment

We have carefully gone through the manuscript again and reformatted addressing the issues pointed out

We have revised the entiremanuscript and added the relevant citations

The background, objective, method, results and conclusions of manuscript need to be reformatted including make them bold. Thank you very much

We have reformatted the subheadings as per the Journal style

Detail comments/suggestions

Title

I suggest the title need to be revised. I think it is a cross sectional study, which is a survey, but the title saying surveillance. Unlike your study, surveillance is an ongoing collection of information to detect changes or it is repeated survey. Thank you very much for the comment

We have amended the title as

A National survey of antibacterial consumption in Sri Lanka

Abstract

The abstract lacks background Thank you very much

We have added background in the revised manuscript

The word WHO, in method section need to be written in full. You should first write the full term before you abbreviated. Full term do not need to be in caps and brackets, just abbreviations. Similarly for ABC in the finding section of abstract. Thank you very much

We have addressed this issue in the abstract as well as in the rest of the manuscript whenever applicable

The sentence “Reserve and watch category antibacterials accounted for 46, 24 and 54% of the total, public and private sector consumption” not clear and needs revisions Thank you very much

We apologize for the error

We have amended in the revised manuscript

Amended sentence is:

Watch category antibacterials accounted for 46%, 24% and 54% of the total, public and private sector consumption respectively

The aim of the study and the conclusion is mismatched. The aim is to describe and quantify, but the conclusion seems comparisons between public and private. The recommendation “Our study has provided the evidence that antibacterial surveillance is possible in resource limited countries and it must be made mandatory” needs revisions. Because, the recommendation is beyond the scope of the study, recommended to other resource limited countries are no appropriate, as the method including sampling procedure used in the study are not allowed to infer to other countries. I also suggest to not use the word mandatory since recommendation are not approached as obligatory Thank you very much. We agree with the comment

We have amended the aim of the study as

To quantify and describe the national antibacterial consumption in Sri Lanka and to examine any differences in the consumption between public and private sector

Conclusion is amended as

A disproportionately higher use of broad spectrum and Watch category antibacterials was observed in the private sector which needs further investigation. This national annual consumption survey highlights the need and provides has provided the opening for establishment of an ABC surveillance in Sri Lanka

I not saw key words. Please add. We have given the key words in the online system

These were the key words: antibacterials; consumption; surveillance; antibacterial resistance; utilization (if possible, we will edit the surveillance as survey in the system)

Background

Revise the typo error (two point after the title) of “Introduction:” Thank you very much

We have corrected this typo error

The paper generally needs serious citation revisions. For example, in the first paragraph only, from five sites that need citations, only one has citation and the rest four are not. Please, also add more evidences/citations for those cited also. Thank you.

We have revised the paper extensively and added citations as appropriate

The third paragraph of introduction also missed citations and needs revised again. Thank you, this has been done. As we have redone the entire paper this is now paragraph 4.

The last paragraph of introduction “therefore conducted a national surveillance of antibacterial consumption (ABC)” needs revisions. Thank you, revised as given below

The Sri Lanka Association of Clinical Pharmacology and Therapeutics (SLACPT), in collaboration the National Focal Point for combating AMR in Sri Lanka, therefore conducted this national survey of antibacterial consumption (ABC) for 2017.

As suggested above to the title, this study is not surveillance rather a survey. The two concepts are quite different. Thank you very much

We have amended the term surveillance to survey

What are the significance of the sentence “This paper outlines the methods adopted, key findings and recommendations for establishment of a national surveillance programme” This sentence has been modified as below:

This paper presents the methods adopted, discusses the key findings and the problems encountered when conducting the survey.

The background section lacks and needs to revise based on updated prior literatures on global, regional and national picture about the antimicrobial consumption. Thank you and the background section has been extensively revised with reference to other studies on global, regional and national AMC.

Authors also need to add contribution of this study and practical policy implication. Thank you, we have added the following:

Our findings would be helpful when planning for comprehensive national AMC surveys or surveillances.

I couldn’t see the aim/s and or objective of the study in this section that is mentioned in the abstract, authors need to expand those points including the rationale of the study. Thank you very much

We have included the objective of the study in the last paragraph of the introduction

Methods

There are many bolded disorganized subsections. No need to say background here. Please reformat them based on the journal style. For instance, study design, data source and sampling procedure in to one subsection. Variables of the study (outcome variable vs explanatory variables, including their definitions with appropriate citations, coding and categories in another subsection. Then, data entry, data analysis, and presentation of results as statistical analysis, the ethical issues in another subsection like that. Thank you very much for the comment

We have reformatted the methods section with three sub section

Materials and Methods

1. Study design and data source

2. Measures of antibacterial consumption

3. Ethical considerations

Information given in the original manuscript had been reassigned to these three sub sections

Please elaborate a little more on the ethical issues. The ethical issues mentioned in the data source section need to be bring in to ethical consideration section. Thank you very much for the comment

We have given some additional information under ethical considerations

Ethics Review Committee of Sri Lanka Medical Association exempted this survey from ethics review committee approval (ERC-18/14), Formal request letter with a copy of ethics review committee approval was sent to all the institutions who had the data. Investigators personally visited many of these institutions to explain the aim of survey. Data presented here are from the consenting institutions. Data comprised aggregate data of amount of antibacterials distributed, imported or manufactured by these institutions and not individual patient or hospital data.

Please summarize data source and availability of data into one. Thank very much

Please see our responses for the first comment in the methods

Authors mentioned as it indicates the 2017 national antimicrobial consumption. However, the data collection period or this specific study is not mentioned. We have already given this information

Second sentence in the methods

It was done in 2018

I couldn’t found about sampling technique and procedures use in the study. Who were the source and sampled population? How they were selected? Based on the medicine supply system in Sri Lanka, the data sources we identified are expected to provide the data for the entire country. So, we did not employ any sampling technique

We have now given one statement to this effect in lines 25 and 26 under methods

These data sources are expected to provide the data for the entire country. Hence, no sampling was done.

Who were the data collectors? What are the tools? Data comprised aggregate data

They were extracted electronically (Excel worksheet) or manually transferred from the paper format of data submitted by the institutions

Hence we have not used data collectors.

We have now given one statement to this effect in lines 30- 32 under methods

Data from the MSD were electronically transferred. All other data sources submitted data in paper format which were manually entered in the Excel worksheet.

Methods- Additional change done by us

In the methods section we have given a formula about calculating defined daily doses. To improve the format of the section, we have converted the formula into text

Number of DDDs consumed was calculated by dividing the total consumption (in grams) by DDDs (in grams).

Results

The results need to be summarized with subsection to make clearer of the key findings. Thank you. We have added subsections as appropriate

Please avoid the typo error (colon after the title of results Thank you and done

Results – Additional change/s done by us

1. We have combined results and discussion under one title as per the journal format

2. Additional column in table 2 - DDD per 1000s population

3. Additional column in table 4 to show the quality indicators for the country

4. Changed figure 2 to tables 5 and 6 to highlight the issues clearly

Discussion

The discussion is poor. It seems redundancy with results, and therefore, needs careful revisions; compare and contrast of your key findings with prior literatures and justify or discuss in details especially for inconsistency findings. It also have citations problem. Thank you. The discussion has been extensively revised to compare and contrast our findings with prior literature. The citations have been updated.

Conclusions

The conclusion is not specific and not aligned with the findings. Please first write the word in full before you abbreviated it such as LMICs. You recommend to LMICS, but I couldn’t see any evidence in the method sections including sampling technique, that support for generalizability of the findings for LMICs. The conclusion is beyond the study’s scope and not specific. Please revise it. Thank you. We have revised the conclusions to reflect our findings.

REVIEWER 3

This is a comprehensive study looking at antibiotic consumption patterns in a LMIC. It is well-written except for a few grammatical errors (Introduction - line 3, page 5 - line 10, page 20 - lines 1 and 6). Thank you. The paper has been revised extensively and we have corrected the errors stated.

Data however is far from complete since many potential sources have not been able to provide usable data (ie only 12/78 private importers have submitted usable data). Agree and we have explained this in our limitations.

Although there were 78 importers registered with NMRA, the exact number of Companies imported antibacterials in 2017 was not available: Rough estimate from NMRA records was 40. Of them, we have got data from 12. Moreover, of the 5 leading importers, we have got data from 4. In addition, the private sector distribution data from SPC could have captured the data for the Companies who have not submitted data to us

We have mentioned in the results section, paragraph 1

A major factor that affects antibiotic consumption in the public hospitals in Sri Lanka is the highly limited formulary that is available for prescribers, compared to the private sector. This fact has not been taken in to account in the Discussion. Being able to 'locally purchase' antibiotics in the public sector does not equate to the choice of antibiotics available in the private sector. Thank you for this suggestion. We have incorporated it to the discussion as below:

A major factor that affects antibiotic consumption in the public hospitals in Sri Lanka is the highly limited formulary available to prescribers. The formulary is based on the WHO’s and the country’s EMLs and the medicines are made available strictly according to it to the public sector institutions. Even though prescribers have the facility of “local purchase” of medicines, this does not give them the same availability of medicines as those practicing in the private sector as the patients who seek care from these institutions are largely those with limited financial means.

No information on antibiotic resistance patterns in the country is provided. Therefore, the usefulness and applicability of the prescription patterns is not explored in detail. Thank you for this suggestion. We have added information on AMR patterns in Sri Lanka both in the Background and results and discussion sections.

Additional changes done by us

a) Surveillance was changed to survey in all places

Submitted filename: Response to reviewers.docx

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6 Jul 2021

PONE-D-21-11873R1

A National Survey of antibacterial consumption in Sri Lanka

PLOS ONE

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Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

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Reviewer #4: section 2.

The manuscript is technically sound, and the information presented were rigorously analyzed.

These are the points that I want the authors to better clarify and that is why I feel there is a little information that is lacking. I also want to recall that the authors specified the scarcity of information related to the topic they surveyed. So, I think the comment I will make here are somehow important for readers to get the most of what was shown, but if it not possible for the authors to fully answered my concerns, then I am not sure it will change the great work that was done:

PAGE 13: it is acknowledged that the public sector provides most inpatient care compared to the private sector, but it is not well explained what is the link/association between inpatient care and high ABC!

Did you ascertain the proportion of outpatient prescription of drugs with that of inpatient? If not, the argument on inpatient needs to be supported by specific references.

The 74.5% of imports to the private sector is in favor of the idea “that the private sector use more drugs for outpatient care than inpatient care”.

What could justify a higher use of macrolides, quinolones and other beta-lactams in the private sector compare to the public?

As all these aspects will have policy implications, it is important to answer (or at least try) these points.

What could also explain the disproportionately higher use of broad spectrum antibacterial in the private sector than in the public?

Page 20 and 21.

[REASONS FOR GREATER USE BRAOD SPECTRUM ANTIBACTERIAL IN THE PRIVATE SECTOR: lack of regulatory oversight, greater accessibility to antibacterial and improved financial status of patients.

REASONS FOR GREATER USE BRAOD SPECTRUM ANTIBACTERIAL IN THE PUBLIC SECTOR: inappropriate prescriptions of antibacterial, incorrect physician perception of the need for antibacterial, high patient volume, fear of bacterial super infection and the limited formulary available to prescriber.] It is difficult to understand how each of these factors affect the use in a different manner in the two different studied setting.

Finally, is it possible to know if in both private or public hospitals, there are some guidelines on antibiotic usage that are put in place to guide physicians or pharmacists in healthcare facilities? The idea is to know if there are some protocols to follow before or during prescription.

Reviewer #5: This is an appreciable work done on a very important reasearch area that acts as a compus for the AMR surveillance strategies . I have made some queries and comments in the annotated file and would appreciate that these are attended to ensure more clarity and for ease in understanding the data processing and interpretation for the complex area of AMC. The readers must be able to understand the data and study design in the context of the country where study is conducted. It is appreciable tha the authors have addressed the comments of previous eviewers diligently

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Reviewer #4: No

Reviewer #5: No

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Submitted filename: Review Plos ONE _HR comments filepdf.pdf

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28 Jul 2021

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice

Thank you

We have reviewed the reference list. It was complete and correct, none of the articles we have cited have been retracted. Unfortunately, WHO has migrated some of their documents and the links had changed after 18th May 2021 which was the time of our initial submission. We have updated the links as of 9th July 2021.

Some of the references from the WHO have compatibility issues with some web browsers and may not be seen with browsers such as Safari.

Reviewer 3 PONE-D-21-11873

These comments are for the older version PONE-D-21-11873 and have been addressed in our submission PONE-D-21-11873R1

Introduction – highlighted words to be deleted This has been addressed in the resubmission PONE-D-21-11873R1

Add another limitation: the fact that you only calculated the doses assuming that only adults used the antibiotics. This has been addressed in the resubmission PONE-D-21-11873R1 (Page 22)

Now, we have added under limitations also (Page 23)

Reviewer 4

PAGE 13: it is acknowledged that the public sector provides most inpatient care compared to the private sector, but it is not well explained what is the link/association between inpatient care and high ABC!

Thank you, Similar to many resource limited countries, in Sri Lanka too, use (and overuse) of ABAs is high in inpatient care. This is because majority of infectious diseases which need antibiotics (septicaemia, meningitis, complicated dengue, pneumonia, etc.) are admitted to hospitals, whereas only patients with mild infections (bacterial pharyngitis, bacterial otitis media, uncomplicated pneumonias and UTIs etc.) are treated as outpatient. In addition, there are limitations in doing bacteriological investigations in outpatient settings. Hence patients that need bacteriological investigations are admitted. Therefore, it is natural to expect high volume of ABC in public sector which handles majority of inpatient care in Sri Lanka. However, this was not the case in our results which showed a higher ABC in the private sector.

Therefore, we have modified the statement to reflect our observation more clearly

Previous statement

Despite most of the inpatient care being provided by the public sector health care institutions, the ABC in the private sector (Table 1; data sources 1, 4 and 7) accounted for 246.76 million DDDs compared to 97.96 million DDDs distributed to the public sector by the MSD (data source 2).

Edited statement in the current submission (Page 12)

In Sri Lanka, most of the inpatient care is provided by the public sector while the outpatient care is shared between the public and private sectors [15]. Despite bulk of patient care being provided by the public sector, the ABC in the private sector (Table 1; data sources 1, 4 and 7) was 246.76 million DDDs compared to 97.96 million DDDs distributed to the public sector by the MSD (data source 2).

Did you ascertain the proportion of outpatient prescription of drugs with that of inpatient? If not, the argument on inpatient needs to be supported by specific references. As we have used procurement data, we did not ascertain the proportion of outpatient and inpatient use. However, in our experience about healthcare structure in Sri Lanka, major infectious diseases (confirmed and suspected) are managed as inpatients in public sector in Sri Lanka. Despite this fact, public sector consumption was only 97.96 million DDDs. Public sector’s greater contribution to inpatient care is supported by reference [15]

The 74.5% of imports to the private sector is in favor of the idea “that the private sector use more drugs for outpatient care than inpatient care”. Thank you and we agree. The following has been added to explain the situation in Sri Lanka. As there are no published studies in this area we have stated our experiences and used the words ‘could be”

Added paragraph (Page 12-13)

The higher ABC of private sector could be due to the significant proportion of outpatient care that is provided by the private sector which includes the private hospitals and independent family physicians in the community. The antibiotics prescribed by these sectors are obtained from the retail pharmacies in the private hospitals and in the community and will contribute towards the increased ABC of the private sector.

What could justify a higher use of macrolides, quinolones and other beta-lactams in the private sector compare to the public?

As all these aspects will have policy implications, it is important to answer (or at least try) these points.

Thank you for the observation. While nothing can justify this high use of broad spectrum and Watch antibiotics by the private sector, we have tried to explain this in the discussion (page 21)as given below:

A significant finding from our survey is the disproportionately higher use of broad-spectrum antibiotics in the private sector when compared to the ABC of the public sector. The disparity is difficult to explain, especially as prescribers in both these sectors being largely the same. In addition, the National Antibiotic Guidelines for empirical treatment of infections [31] have been widely disseminated to the prescribers and they are expected to adhere to these irrespective of the place of practice. A major factor that affects antibacterial consumption in the public hospitals in Sri Lanka is the highly limited hospital formulary available to prescribers. The formulary is based on the country’s EMLs and the medicines are made available strictly according to it to the public sector institutions. Even though prescribers have the facility to “local purchase” medicines, this does not give them the same availability of medicines as those practicing in the private sector as the patients who seek care from these institutions are largely from lower income segments of the society. The freedom to prescribe any medicine that is available in the country and improved financial status of the patients who seek treatment from the private sector could contribute to the greater use of broad-spectrum and newer antibiotics in the private sector.

What could also explain the disproportionately higher use of broad spectrum antibacterial in the private sector than in the public?

Thank you for the comment, we have added the following in page 19 and the possible reasons are discussed in pages 21 in detail (see above comment)

While both sectors have consumed large amounts of oral and parenteral antibacterials in the Watch category, this is much more in the private sector. Notable is the disparity in the consumption of ceftriaxone, cefuroxime and meropenem. This is a concern as it would contribute significantly towards the spread of antibiotic resistant organisms in the country

Page 20 and 21.

[REASONS FOR GREATER USE BRAOD SPECTRUM ANTIBACTERIAL IN THE PRIVATE SECTOR: lack of regulatory oversight, greater accessibility to antibacterial and improved financial status of patients.

REASONS FOR GREATER USE BRAOD SPECTRUM ANTIBACTERIAL IN THE PUBLIC SECTOR: inappropriate prescriptions of antibacterial, incorrect physician perception of the need for antibacterial, high patient volume, fear of bacterial super infection and the limited formulary available to prescriber.] It is difficult to understand how each of these factors affect the use in a different manner in the two different studied setting.

Thank you. We have explained the reasons in the discussion (Pages 19-21.) “lack of regulatory oversight” has been removed as it does not give the correct picture.

Paragraph in the current version:

A significant finding from our survey is the disproportionately higher use of broad-spectrum antibiotics in the private sector when compared to the ABC of the public sector. The disparity is difficult to explain, especially as prescribers in both these sectors being largely the same. In addition, the National Antibiotic Guidelines for empirical treatment of infections [31] have been widely disseminated to the prescribers and they are expected to adhere to these irrespective of the place of practice. A major factor that affects antibacterial consumption in the public hospitals in Sri Lanka is the highly limited hospital formulary available to prescribers. The formulary is based on the country’s EMLs and the medicines are made available strictly according to it to the public sector institutions. Even though prescribers have the facility to “local purchase” medicines, this does not give them the same availability of medicines as those practicing in the private sector as the patients who seek care from these institutions are largely from lower income segments of the society.

The freedom to prescribe any medicine that is available in the country and improved financial status of the patients who seek treatment from the private sector could contribute to the greater use of broad-spectrum and newer antibiotics in this setting.

This statement is based on two studies done to assess antibiotic prescription in the outpatient setting of the public sector in Sri Lanka.

We have modified the sentences as given below for clarity: (Page 21-22)

However, inappropriate prescriptions of antibacterials are seen in the outpatient management of respiratory infections in the public sector hospitals too [32,33]. Patients demand for antibiotics as a “quick fix” for infections, incorrect physician perception of the need for antibacterials, fear of bacterial superinfection in viral diseases and the high patient volume in the outpatient settings which limits time for assessment have led to a greater prescription of broad-spectrum antibiotics [ 33].

Finally, is it possible to know if in both private and public hospitals, there are some guidelines on antibiotic usage that are put in place to guide physicians or pharmacists in healthcare facilities? The idea is to know if there are some protocols to follow before or during prescription. Thank you and yes there are national guidelines for empirical and prophylactic use of antimicrobials [31]. We have added this.

Reviewer #5 - PONE-D-21-11873R1

Reviewer #5: This is an appreciable work done on a very important research area that acts as a compus for the AMR surveillance strategies. I have made some queries and comments in the annotated file and would appreciate that these are attended to ensure more clarity and for ease in understanding the data processing and interpretation for the complex area of AMC. The readers must be able to understand the data and study design in the context of the country where study is conducted. It is appreciable that the authors have addressed the comments of previous reviewers diligently Thank you

Page 10 Para 1

Describe if any list was provided to the respondents or they were left to decide by themselves for medicines with antibacterial effect. It is presumed that the data was invited for all antibacterials irrespective of their EML listing status/.Please clarify Thank you, Yes, data were requested irrespective of their EML/Formulary status. We provided the ATC code {antibacterials for systemic use (J01)} for those who had the data in ATC format (e.g. MSD, SPC). For others, we provided a list containing the names of antibacterials categorized under TC code antibacterials for systemic use (J01)

We have added the following sentence in page 8

Details of all antibacterials were requested irrespective of their EML or Sri Lankan Formulary listing status. We provided the ATC code (J01) for those who had the data in the ATC format and a list containing the names of antibacterials categorized under J01 for those who did not have the data in the ATC format.

Page 10 - Methodology

methodology states that data i calculated in DDDs using adult dosages. Were consumption data adjusted for syrups excluding them or keeping a percentage. What is the Sri Lankas population proportion for paediatric and geriatric patients Thank you for the comment

In Sri Lanka, liquid preparations are not used in geriatric population as they are expensive. Since the dose required for elderly is higher, the requirement of liquid preparations could be many times more than that is required for children. Neither the country nor the great majority of patients can afford this. Even for children, liquid preparations are not uniformly available (Indian J Pediatr 2021. Feb;88(2):178-179.doi: 10.1007/s12098-020-03409-6. Epub 2020 Jun 20.

Percentage of children (0-5 years) in Sri Lanka is about 8.5%

Using the DDDs for adults when there is paediatric consumption also is an inherent limitation of drug utilization surveys. We have noticed this limitation in other published articles as well. Hence, we have not done any adjustment. We have stated this as a limitation (Page 22, 23)

Mention, in Limitation the concerns related to paediatric patients Thank you, we had done this in PONE-D-21-11873R1 under limitations in page 22 and this is what we have said:

“However, the DDD may not reflect the prescribed daily dose (PDD) for individual patients and cannot be used to measure consumption in paediatric wards since the measure is based on adult dosing [36]. It also does not accurately measure antibacterial consumption in cases of renal or hepatic dysfunction, often underestimating the actual antibacterial usage [36].”

Please explain how you have identified duplication of data while the same consumption of supply might be mentioned by manufacturer/importer and the distributor. Figure 1 shows the supply chain of medicines in Sri Lanka and it shows that there is minimal chance of duplication of data. MSD is the sole supplier of medicines to the public sector. Limitation was “non-responders” and “submission of incomplete data that could not be analysed” mainly the private importers. We have mentioned this in the Results (page 20) and limitations (page 22/23)

Mention the source (This is given near Aware Classification) We have modified this as follows in page ….

AWaRe classification 2019 [9] Page 4

Which AWaRe classification if from WHO was used . If it was AWaRe 207 what strategy was adopted for class assignment to medicine shared in access and watch group both As cited, we have used the 2019 AWaRe classification

Ethical Consideration Page 10

at any place has it been mentioned that the institutional and personnel identity contributing to the data will be kept anonymous and coded names or ID will be used in data acquisition and processing

Thank you for the comment. We have not mentioned this. This national survey was done as a service requirement and the identity of the participating institutions was essential to identify the gaps. As such the participating institutions were not deidentified and they have consented to submit data with that understanding. This is the reason for us not to publicly share the raw data as requested by the Journal.

The personnel providing the data have done it in their official capacity and have been identified only as the Institution.

Results and discussion

Use lower case for companies please Thank you, we have corrected these typos.

Though dosage form data had been collected but still no discussion and results were shared to help interpret the results and form comparison among the two sectors.

Thank you. We had discussed all our findings. Tables 5 & 6 compares the top 10 oral and parenteral ABC in the two sectors. The following has been added (page 19)

While both sectors have consumed large amounts of oral and parenteral antibacterials in the Watch category, this is much more in the private sector. Notable is the disparity in the consumption of ceftriaxone, cefuroxime and meropenem. This is a concern as it would contribute significantly towards the spread of antibiotic resistant organisms in the country.

Again the point that if the data is not adjustable to accommodate the paediatric doses (and only used adult DDDs) then why syrup and suspension formulations remained included the consumption data. The proportion could have been easily shared here in data to access the margin of error created, even if pooled data (Oral liquid forms inclusive data) was used for the discussion of the overall data.

Thank you

As indicated earlier, liquid preparations are not extensively used due to cost difference

This is the proportion of liquid preparations in different data sources (in million DDDs). DDDs for liquid preparations were also calculated using adult DDD

Total Liquid

Distributed by SPC to private sector 163.04 19.75

Distributed by MSD to public sector 97.96 1.56

Imported by private sector 61.18 None

Distributed by SPMC to both to public and private sector 59.30 3.2

Manufactured by SPMC 56.08 None

Distributed by SPC to MSD 31.43 1.15

Distributed by SPC to its retail pharmacies (Rajya Osusala) 24.41 1.13

Only a negligible amount has been contributed by the liquid preparations

It is understandable that the data acquisition in this area is a difficult task. It will be helpful that the supply chain process or hierarchy be depicted pictorially and so that its clear to identify the niche of each respondent organization and see if the data has chance of being duplicated Thank you and we have added Figure 1: the antibiotic supply chain in Sri Lanka for clarity but would like to retain table 1 as it is important for the discussion.

At the moment its manufacturer, importer and distributor data under discussion. Countries vary in their distribution and supply chain processes. The Local purchase discussion do not fit into this context as this is presumably a retail and hospital level transaction Thank you and we agree. We have deleted the section on local purchase. The antibiotics obtained as local purchase are from retail pharmacies and this could have been captured elsewhere.

Table 1

A graphic representation of the results as flow diagram would have been more helpful showing various sources and receiving sectors Thank you and we have added Figure 1: the antibiotic supply chain in Sri Lanka for clarity but would like to retain table 1 as it is important for the discussion.

References New reference 31 has been added and all references have been checked to ensure that they are current and are cited appropriately.

Submitted filename: Responses to Reviewers comments.docx

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18 Aug 2021

PONE-D-21-11873R2

A National Survey of antibacterial consumption in Sri Lanka

PLOS ONE

Dear,

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.

Please include the following items

1-Please provide detail limitation of study after discussion.

2-Please indicate generalizability of findings.

3-Please provide detail recommendation as separate heading for policy makers.

Please submit your revised manuscript by 1st September 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Please include the following items

1-Please provide detail limitation of study after discussion.

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Comments to the Author

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Reviewer #4: All comments have been addressed

Reviewer #6: All comments have been addressed

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2. 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 #4: Yes

Reviewer #6: Yes

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

Reviewer #4: Yes

Reviewer #6: Yes

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #4: Yes

Reviewer #6: Yes

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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #4: Yes

Reviewer #6: Yes

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Reviewer #4: (No Response)

Reviewer #6: (No Response)

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26 Aug 2021

Comment Response

Please provide detail limitation of study after discussion

Thank you

During the last revision, we had already included the paragraph given below at the end of the discussion. We hope this is adequate.

No changes have been made now

“An important limitation of our study was the inability to capture all national data. This was largely due to incomplete and inadequate record keeping by the Customs and private importers. The inability of the SPMC to provide consumption data based on the sector to which it supplied added to the incomplete national consumption data. For meaningful interpretation of data, the total numbers of DDDs derived as consumption estimates should be adjusted for the population to which the data apply. Despite these limitations we have adjusted for the population (DID) to compare with similar studies as there is no separate DDD for children (21). Therefore, we had to use the DDDs for adults in the calculations although both adults and children would have consumed the antibacterials. “

Please indicate generalizability of findings Thank you

We have added this statement at the end of discussion

This is the first time an attempt has been made to document the national consumption of antibacterials in Sri Lanka. While there are some limitations and the actual consumption could be an under estimation, we are confident that the pattern of antibacterial use documented in this paper is unlikely to change even if we have all the whole data on antibacterial consumption. The generalizability of our findings would depend on the systems in place to regulate and survey antibacterial consumption. The paper highlights the need for better regulation of antibacterial consumption and the need for robust surveillance systems. The latter could be both labour and resource intense to LMICs like Sri Lanka.

Please provide detail recommendation as separate heading for policy makers Thank you

We have added the following paragraphs at the end of the body of the manuscript. A new reference is added (38)

Recommendations for policy makers

We strongly recommend the establishment of robust and sustainable surveillance systems to periodically survey and monitor antibacterial consumption. A central body to coordinate the activities of antibacterial consumption is crucial. Surveillance systems should be developed, and adequate funding and resources to collect and analyze data should be made available. All data should be coded at the point of entry using the ATC classification which would help in analysis of data and to compare the consumption trends with other countries.

The data on ABC should be linked with that of AMR to identify trends of antibacterial use and changes in antibacterial sensitivity patterns. The ABC should be reviewed annually to identify trends of use and to regularize antibacterial consumption. Based on the surveillance data, national policies and guidelines for antibacterial use should be developed and measures should be in place to ensure that they are adhered to. Linking up with the WHO programme that has been introduced for LMICs [38] is important to compare the country’s activities with others.

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1 Sep 2021

A National Survey of antibacterial consumption in Sri Lanka

PONE-D-21-11873R3

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6 Sep 2021

PONE-D-21-11873R3

A National survey of antibacterial consumption in Sri Lanka

Dear Dr. Sri Ranganathan:

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