Literature DB >> 33079967

Purchase and use of antimicrobials in the hospital sector of Vietnam, a lower middle-income country with an emerging pharmaceuticals market.

Vu Quoc Dat1,2,3, Phan Khanh Toan1, H Rogier van Doorn3,4, C Louise Thwaites3,4, Behzad Nadjm3,5.   

Abstract

INTRODUCTION: Antimicrobial use is associated with emergence of antimicrobial resistance. We report hospital antimicrobial procurement, as a surrogate for consumption in humans, expenditure and prices in public hospitals in Vietnam, a lower middle-income country with a high burden of drug resistant infections.
METHOD: Data on antimicrobial procurement were obtained from tender-winning bids from provincial health authorities and public hospitals with detailed bids representing 28.7% (1.68 / 5.85 billion US $) of total hospital medication spend in Vietnam. Antimicrobials were classified using the Anatomical Therapeutic Chemical (ATC) Index and the 2019 WHO Access, Watch, Reserve (AWaRe) groups. Volume was measured in number of Defined Daily Doses (DDD). Antimicrobial prices were presented per DDD.
RESULTS: Expenditure on systemic antibacterials and antifungals accounted for 28.6% (US $482.6 million/US $1.68 billion) of the total drug bids. 83% of antibacterials (572,698,014 DDDs) by volume (accounting for 45.5% of the antibacterials spend) were domestically supplied. Overall, the most procured antibacterials by DDD were second generation cephalosporins, combinations of penicillins and beta-lactamase inhibitors, and penicillins with extended spectrum. For parenteral antibacterials this was third generation cephalosporins. The average price for antibacterials was US $15.6, US $0.86, US $0.4 and US $11.7 per DDD for Reserve, Watch, Access and non-recommended/unclassified group antibacterials, respectively.
CONCLUSIONS: Antimicrobials accounted for a substantial proportion of the funds spent for medication in public hospitals in Vietnam. The pattern of antibacterial consumption was similar to other countries. The high prices of Reserve group and non-recommended/unclassified antibacterials suggests a need for a combination of national pricing and antimicrobial stewardship policies to ensure appropriate accessibility.

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Year:  2020        PMID： 33079967      PMCID： PMC7575121          DOI： 10.1371/journal.pone.0240830

Source DB:  PubMed          Journal:  PLoS One        ISSN： 1932-6203            Impact factor:   3.240


Introduction

Despite concerted international efforts, antimicrobial use continues to rise in both humans and animals. Data on antibacterial sales from 76 countries (including Vietnam) between 2010 and 2015 estimated global antibacterial consumption in humans has increased by 65% over this period, reaching 42 billion defined daily doses (DDDs) every year [1]. Global consumption is forecast to increase by a further 200% between 2015 and 2030 if there are no changes in current practice [1]. The difference in overall antibacterial consumption between the highest and lowest -consuming countries was 3-fold for total use (in DDDs per 1 000 population per day), and up to 16 fold in volume for quinolones and cephalosporins among the (mostly high-income) countries in the Organisation for Economic Co-operation and Development (OECD) [2]. Antibacterial consumption was positively correlated with growth in per capita gross domestic product (GDP) [1] and low- and middle-income countries (LMICs) are consequently responsible for driving the rise in global antibacterial consumption [3]. From 2000 to 2010, Brazil, Russia, India, China and South Africa contributed 30% of global population growth but 76% of the increase in global antibacterial consumption (in number of doses) in the same period [3]. There is a positive correlation between antibacterial consumption and levels of bacterial resistance to antibacterials [4]. In 2017, WHO introduced the AWaRe classification of antibacterials (Access, Watch and Reserve groups) to promote antimicrobial stewardship at local, national and global level, and address the challenge of increased antimicrobial resistance. The ‘Access’ group includes first and second choice antibacterials for the empirical treatment of common infectious syndromes which should be widely available in all healthcare settings. The ‘Watch’ group includes antibacterial classes, against which there is a higher resistance potential and are recommended for a limited number of indications. Finally, the ‘Reserve’ or last resource group includes antibacterials that are recommended for highly specific situations when all alternatives have failed [5]. In October 2019, WHO revised the AWaRe classification to include several antibacterials (mostly second generation cephalosporins) which were not classified in the 2017 version in the 3 existing categories; to classify non evidence-based fixed dose combinations of antibacterials as ‘Not recommended’ and to link antibacterials with the Anatomical Therapeutic Chemical (ATC) codes and WHO Essential Medicines List [6]. WHO recommends that countries monitor the consumption of the Watch and Reserve antibacterials carefully as part of their AMR strategy [5] and to inform policies which optimize their use in a timely manner [7]. Vietnam is a LMIC with a population of 94.6 million and GDP per capita of US $2,171 [8]. In 2016, health expenditure accounted for 5.7% of GDP, corresponding to annual per capita health expenditure of US $122.8, 45% of which was out of pocket spending [8]. Vietnam has one of the highest rates of antimicrobial drug resistance in Asia. In an antimicrobial resistance surveillance network of 16 hospitals in Vietnam between 2012 and 2013, the proportion of antimicrobial resistance was high among all pathogens isolated from clinical specimens: penicillin non-susceptible Streptococcus pneumoniae (67%, 229/344 isolates), methicillin-resistant Staphylococcus aureus (MRSA) (69%, 1098/1580 isolates), third-generation cephalosporin-resistant Escherichia coli (56%, 2342/4192 isolates) and Klebsiella pneumoniae (66%, 1479/2227 isolates), carbapenem-resistant Pseudomonas aeruginosa (33%, 578/1765 isolates) and carbapenem-resistant Acinetobacter spp. (70%, 1495/2138 isolates) [9]. However, due to lack of resources for collecting reliable data and maintaining surveillance system, data on antibacterial consumption from LMICs are still limited and of poor quality, especially for countries from Southeast Asia [10]. In addition to quantifying consumption of antimicrobials, understanding relative prices and purchases of antimicrobials is important since their consumption is associated with antimicrobial resistance but a high price of medication may act as a barrier to access, reducing consumption. Our study reports the availability and price of antibacterials and estimates their usage in public hospitals in Vietnam.

Materials and methods

Study approach

Data on antimicrobial procurement were obtained from tender-winning bids from 52/63 provincial health authorities and 30 public hospitals across Vietnam for 2018. The process of bidding for contracts to supply medication to public health facilities follows Vietnamese government guidance [11].The current medication procurement in Vietnam is mostly implemented through bidding which uses a decentralised (individual hospitals directly conduct the procurement) or centralised model (at national level by ministry of health or at provincial level by provincial departments of health, DoHs). At provincial level, centralised procurement involves provincial DoHs gathering procurement needs of provincial and districts hospitals under their jurisdiction, calling for, reviewing and accepting bids. Hospitals’ estimated requirements for antibacterials are based on consumption in the previous year. Payment is made by the hospitals regardless of whether a decentralised or centralised bid model was used. As part of the procurement regulations, the health facility is expected to ensure the consumption of at least 80% of each medication purchased [11]. The tender-winning bids used for the study comprised 52/63 Provincial Departments of Health, 23 secondary hospitals and 7 primary hospitals (outside the 52 provincial departments) throughout Vietnam. As of December 2017, Vietnam had 13,583 public healthcare facilities, including 1,085 hospitals with 308,400 patient beds, 579 regional clinics and 11,830 medical service units in communes, wards, offices and state- or privately-owned enterprises [12, 13]. In the private sector, there were 231 private hospitals with 16,000 beds (approximately 5% of national hospital beds) in the country by 2019 [14]. The country’s public healthcare system is divided into four technical categories: tertiary hospitals (under administrative control of or appointed by the Ministry of Health), secondary hospitals (under the DoHs and catering to and receiving referrals from the province population), primary hospitals (district hospitals under Provincial DoH, catering to and receiving referrals from the district population and commune health stations), and commune health stations or medical service units [15, 16]. Currently there are 75 tertiary hospitals, 491 secondary hospitals, 514 primary hospitals and 5 unclassified hospitals [12].

Data resources

Data on the price and characteristics of procured antimicrobials in Vietnam were taken from the successful tenders for medicines in 2018 for hospitals and provincial DoHs in Vietnam as published on the website of the Drug Administration of Vietnam which is the Ministry of Health regulatory authority [17]. The bid winning tenders from provincial DoHs may cover all or only some of the primary and/or secondary hospitals within that province and the data on precisely which hospitals, or the breakdown by type within each bid, were not available. All successful bids with available data were used for this analysis (S1 Fig). The data for each tender included the name of the active ingredient, trademarks, strength, dosage and package, route of administration, registration identification, manufacturer, country of origin of manufacturer, measuring unit, bid quantity, unit price, total value, bidders, suppliers and brand name/generic name [11]. The list of drugs in our analysis excluded antimicrobial medications which are nationally procured, such as those for the treatment of HIV, influenza, tuberculosis and malaria. The medications procured would be dispensed for inpatients and outpatients in the hospital sector. We described the antimicrobial manufacturers by their country of origin to estimate the market shares between domestic and international manufacturers which may provide some insight into manufacturing capacity.

Estimation of antimicrobial procurement and the price to the hospitals

Currently, there are no national stewardship programmes defining access to different antimicrobials but individual hospitals may have their own policies on their use. All antimicrobials for systemic use were included in the analysis and classified using the Anatomical Therapeutic Chemical (ATC) Index with Defined Daily Doses (DDDs) 2018 [18]. The DDD is recommended by WHO as a measurement unit of drug consumption [19]. It is the average maintenance dose of a drug per day for a 70 kg adult for its main indication. It provides an estimate and comparison of drug consumption between population groups and is widely used in pharmacoeconomical studies. The DDD for a given drug is assigned by ATC/DDD classification with a unique code and may be different for the routes of administration (oral and parenteral) of the same drug when there is a substantially difference of bioavailability. It is neither defined for topical products nor available for all drug combinations [20]. Antibacterials were further classified by 2019 AWaRe categories [6]. In this analysis, price was defined as a monetary value of an antimicrobial established in successful bids and calculated per DDD. We calculated the total DDD procured for an antimicrobial by multiplying the total procured at each dose-route of administration for this drug by the DDD conversion factor for the corresponding dose-route of administration. The average price per DDD of an antimicrobial drug was calculated by dividing bidding price for that drug by the total number of DDD. The high/low ratio was used to compare the difference between the highest unit price and the lowest price of one DDD of each antimicrobial across all the tenders. All prices were converted from VND to US $ according to the annual average official exchange rates of the World Bank in 2017 (US $1 = 22,370.09 VND) [21]. The average price of antimicrobials per DDD, the share of antimicrobials bidding price in the hospital drug spend and the number of DDD are used to compare in different levels of hospitals. Pareto chart (ABC analysis) was used to examine the consumption of antimicrobials and expenditures for procurement [22, 23]. The ratio of the highest to the lowest price of antimicrobials per DDD (high/low (H/L) ratio) was calculated to report the variation of antimicrobials price [24]. Spearman correlation coefficient was used to assess the association between variation of antimicrobials prices (high/low ratio) and number of manufacturers. Descriptive statistics were performed using Microsoft Excel (Office 365, version 1909, Microsoft Corporation, Redmond, Washington,).

Results

We included tender-winning results totalling US $1.68 billion from 23 secondary hospitals, 7 primary hospitals and 52 provincial departments of health in Vietnam. This excludes disposable and consumable medical supplies and medical equipment. The estimated total pharmaceutical sales in Vietnam in 2018 was US $ 5.85 billion [25], our analysis (US $1.68 billion) is therefore estimated to represent 28.7% of the funds spent on medication nationally. The overall spending on systemic antibacterials and antifungals accounted for 28.6% (US $482.6 million) of the total funds spent on drugs for the study hospitals (Table 1).
Table 1

Expenditure and number of DDD.

Department of Health (n = 52)Secondary hospital (n = 23)Primary hospital (n = 7)All sites
J01_antibacterials for systemic useTotal expenditure (%)US $430,713,755 (29.50%)US $47,888,882 (22.01%)US $1,426,924 (18.49%)US $480,029,561 (28.48%)
Number of DDD (%)636,851,337 (93.26%)51,468,583 (95.32%)4,036,865 (96.62%)692,356,785 (93.43%)
J02_antimycotics for systemic useTotal expenditure (%)US $1,750,265 (0.12%)US $815,819 (0.37%)US $13,898 (0.18%)US $2,579,982 (0.15%)
Number of DDD (%)2,342,056 (0.34%)US $219,822 (0.41%)20,798 (0.50%)2,582,676 (0.35%)
P01_antiprotozoalsTotal expenditure (%)US $940,694 (0.06%)US $17,942 (0.01%)US $1,577 (0.02%)US $960,214 (0.06%)
Number of DDD (%)9,657,984 (1.41%)406,181 (0.75%)34,875 (0.83%)10,099,040 (1.36%)
P02_anthelminticsTotal expenditure (%)US $436,790 (0.03%)US $68,622 (0.03%)US $2,369 (0.03%)US $507,781 (0.03%)
Number of DDD (%)4,735,531 (0.69%)590,841 (1.09%)17,250 (0.41%)5,343,622 (0.72%)
Other medications (non-antimicrobial)Total expenditure (%)US $1,026,229,647 (70.29%)US $167,855,286 (77.16%)US $6,225,722 (80.66%)US $1,188,532,427 (70.52%)
TotalTotal espenditure (%)US $1,460,071,152 (100.00%)US $217,553,353 (100.00%)US $7,718,581 (100.00%)US $1,685,343,086 (100.00%)
Number of antimicrobial DDD (%)682,893,636 (100.00%)53,994,079 (100.00%)4,178,096 (100.00%)741,065,810 (100.00%)
Among antibacterials for systemic use (J01), there were a total of 77 different substances (ATC 5th level) in 23 chemical subgroups (ATC 4th level) procured over all sites. Antibacterials procured according to their AWaRe categories are presented in Fig 1. The Access group, and Watch group antibacterials accounted for 47.2% and 52.4 of procured number of antimicrobial DDD respectively whilst the Reserve group accounted for 0.1% of antibacterials procured. We identified 4 antibacterials that were unclassified by the 2019 AWaRe classification (ticarcillin with a beta-lactamase inhibitor (J01CR03), nalidixic acid (J01MB02), norfloxacin and tinidazole (J01RA13) and tinidazole (J01XD02)) but remain recommended by national treatment guidelines for specific infections. The proportion of AWaRe non-recommended/unclassified antibacterials were 0.3% of total DDD numbers in all settings. The proportion of Access group, Watch group, Reserve group and non-recommended/unclassified antibacterials provided by domestic manufacturers were 82.2%, 83.3% and 44.3% and 65.7% respectively.
Fig 1

Proportional antibacterial procurement in DDD (%) by AWaRe classification.

Oral antibacterials accounted for 91.4% of total DDD of antibacterials (J01) across all sites (Fig 2). Parenteral antibacterials represented 11.2% of the procured antibacterial DDDs in secondary hospitals, 3.8% in primary hospitals and 8.5% in bids by DoH. The most common oral antibacterials across all sites were the second generation cephalosporins (J01DC) (cefoxitin, cefamandole, cefmetazole, cefotiam, cefaclor and cefuroxime) (19.8% of total DDD). When stratified by the site of procurement, the most commonly procured oral antibacterials in secondary hospitals were combinations of penicillins and beta-lactamase inhibitors (J01CR) (29%) and in primary and departments of health hospitals were the second generation cephalosporins (J01DC) (21.8% and 20.3% respectively). For parenteral antibacterials, the most common antibacterials were the third generation cephalosporins (J01DD) (29.1%). The details of antibacterial procurement in DDD is shown in Table 2.
Fig 2

The proportion of bidding price and number of DDD of antimicrobials for systemic antibacterial (J01) by route of administration in hospitals in Vietnam.

Table 2

The proportions of total DDD and expenditure of antibacterials for systemic use (J01).

Department of HealthSecondary hospitalsPrimary hospitalsAll sites
% DDD% expenditure% DDD% expenditure% DDD% expenditure% DDD% expenditure
J01DC_Second generation cephalosporins20.29%16.52%19.66%8.06%21.81%15.87%20.25%15.67%
J01CR_Combinations of penicillins, incl. beta lactamase inhibitors16.31%15.77%26.33%15.22%18.35%24.10%17.06%15.74%
J01CA_Penicillins with extended spectrum15.78%2.94%10.67%0.91%11.89%2.21%15.38%2.74%
J01DD_Third generation cephalosporins12.23%23.02%19.73%23.31%8.55%24.86%12.77%23.05%
J01MA_Fluoroquinolones11.33%11.56%12.89%14.89%11.54%7.94%11.45%11.89%
J01DB_First generation cephalosporins9.00%8.16%0.80%0.57%15.00%8.52%8.43%7.40%
J01FA_Macrolides8.22%3.41%4.05%1.31%9.20%8.81%7.91%3.22%
J01AA_Tetracyclines1.79%0.07%1.78%0.47%2.13%0.08%1.79%0.11%
J01CE_Beta lactamase sensitive penicillins1.59%0.08%0.07%0.00%0.39%0.03%1.47%0.07%
J01EA_Trimethoprim and derivatives0.97%0.18%0.22%0.01%0.11%0.01%0.91%0.16%
J01GB_Other aminoglycosides0.86%1.63%1.45%1.27%0.72%0.84%0.90%1.59%
J01XD_Imidazole derivatives0.40%1.29%0.48%0.81%0.05%0.22%0.40%1.24%
J01CF_Beta lactamase resistant penicillins0.39%0.90%0.18%0.29%0.05%0.13%0.37%0.83%
J01FF_Lincosamides0.22%0.74%0.22%0.93%0.00%0.00%0.22%0.76%
J01DH_Carbapenems0.18%9.18%0.50%18.74%0.04%1.27%0.20%10.12%
J01DE_Fourth generation cephalosporins0.15%2.25%0.29%3.43%0.05%2.04%0.16%2.37%
J01MB_Other quinolones0.14%0.05%0.01%0.00%0.04%0.04%0.13%0.05%
J01XX_Other antibacterials0.05%0.69%0.37%3.09%0.04%0.76%0.08%0.93%
J01XA_Glycopeptide antibacterials0.05%0.69%0.23%2.78%0.03%1.05%0.06%0.90%
J01BA_Amphenicols0.03%0.03%0.00%0.00%0.01%0.01%0.03%0.02%
J01XB_Polymyxins0.01%0.84%0.07%3.90%0.01%1.19%0.02%1.15%

The cells were colorized with red-yellow-green color scale by column. The highest values in a column were red, the average values were yellow, and the lowest values were green. DDD = Defined Daily Dose.

The cells were colorized with red-yellow-green color scale by column. The highest values in a column were red, the average values were yellow, and the lowest values were green. DDD = Defined Daily Dose. The price of antibacterials relative to DDD and bidding cost are shown in Table 3. The second generation cephalosporins (J01DC), combinations of penicillins, including beta lactamase inhibitors (J01CR), penicillins with extended spectrum (J01CA), third generation cephalosporins (J01DD) and fluoroquinolones (J01MA) accounted for 76.6% of all DDD, reaching 65.7% of the total spend across all sites. However, carbapenems (J01DH) only accounted for 0.3% of antibacterial use but 10.2% of the total spent on antibacterials (Fig 3).
Table 3

Prices of antimicrobials.

AntimicrobialsAllOral formulationParenteral formulation
Number of samplesNo. Mfr.Average price per DDDHigh/low ratioNumber of samplesNo. Mfr.Average price per DDDHigh/low ratioNumber of samplesNo. Mfr.Average price per DDDHigh/low ratio
J02AX04_caspofungin71284.531.10--71284.531.10
J01DH04_doripenem10485.311.56--10485.311.56
J01AA12_tigecycline10165.361.00--10165.361.00
J01XB01_colistin84549.982.18--84549.982.18
J01CR03_ticarcillin and beta lactamase inhibitor64240.873.56--64240.873.56
J01DH51_imipenem and cilastatin1832135.716.33--1832135.716.33
J01CA12_piperacillin15234.881.80--15234.881.80
J01DH02_meropenem2692130.9812.90--2692130.9812.90
J01DC01_cefoxitin1451326.578.32--1451326.578.32
J01DH03_ertapenem15124.691.00--15124.691.00
J01CR05_piperacillin and beta lactamase inhibitor1511418.513.90--1511418.513.90
J01DE02_cefpirome72918.003.59--72918.003.59
J01XA02_teicoplanin69517.752.23--69517.752.23
J01DD62_cefoperazone and beta lactamase inhibitor1962116.5627.33--1962116.5627.33
J01DC03_cefamandole66815.884.35--66815.884.35
J01DB03_cefalotin70414.551.77--70414.551.77
J01CR01p_ampicillin and beta lactamase inhibitor1591211.556.06--1591211.556.06
J02AA01_amphotericin B23211.3012.10--23211.3012.10
J01DC09_cefmetazole75810.063.06--75810.063.06
J01XX01_fosfomycin15489.122.814425.131.52110610.312.62
J01DD07_ceftizoxime108157.956.18--108157.956.18
J01DD12_cefoperazone134157.8312.68--134157.8312.68
J01FA10p_azithromycin2167.626.90--2167.626.90
J01XA01_vancomycin166157.572.57--166157.572.57
J01DE01_cefepime157167.1819.53--157167.1819.53
J01MA14_moxifloxacin225166.9337.696170.925.38164912.093.06
J01CR02p_amoxicillin and beta lactamase inhibitor149126.586.52--149126.586.52
J01DB12_ceftezole67106.072.90--67106.072.90
J01DD02_ceftazidime305265.0711.56--305265.0711.56
J01GB07_netilmicin9094.993.43--9094.993.43
J01XX08_linezolid3284.6740.451741.701.5715424.763.68
J01XD02_tinidazole2544.612.98--2544.612.98
J01DD04_ceftriaxone263283.5140.26--263283.5140.26
J01DC07_cefotiam40103.054.00--40103.054.00
J01DD01_cefotaxime285292.7712.18--285292.7712.18
J01DB04_cefazolin9292.464.18--9292.464.18
J01FF01_clindamycin189132.4039.5866100.439.1112335.263.93
J01DD14_ceftibuten1522.372.461522.372.460-
J01GB06_amikacin202122.258.33--202122.258.33
J01CF02_cloxacillin10792.0534.204130.955.186664.764.94
J01XD01_metronidazole160131.934.52--160131.934.52
J01GB01_tobramycin99161.268.75--99161.268.75
J02AC02_itraconazole148111.12308.00139100.716.339182.611.00
J01CF04_oxacillin8160.8511.502730.592.505431.673.14
J01MA12_levofloxacin587390.81495.43233200.2772.13354195.0712.04
J01DD13_cefpodoxime230270.7627.03230270.7627.03--
J01DC04_cefaclor372210.6465.52372210.6465.52--
J01DD15_cefdinir174190.6429.79174190.6429.79--
J01CA01_ampicillin8560.637.10110.121.008450.632.88
J01MA06_norfloxacin2060.6118.732060.6118.73--
J01CE01_benzylpenicillin4140.615.40--4140.615.40
J02AC01_fluconazole173180.60142.46159160.4680.3014212.021.47
J01MA03_pefloxacin3450.5812.501230.141.712221.101.27
J01MA02_ciprofloxacin518390.561899.69222240.0842.81296158.8531.10
J01BA01_chloramphenicol4390.525.252480.462.021911.341.14
J01FA02_spiramycin194170.459.07194170.459.07--
J01DB09_cefradine9680.4312.767850.4212.761830.743.62
J01CR02o_amoxicillin and beta lactamase inhibitor965330.3823.70965330.3823.70--
J01DB05_cefadroxil254240.3724.89254240.3724.89--
J01DD08_cefixime550310.3452.05550310.3452.05--
J01DB01_cefalexin304200.3116.47304200.3116.47--
J01MA01_ofloxacin124180.27677.9797140.0410.172748.426.53
J01FA09_clarithromycin356230.2719.19356230.2719.19--
J01FA10o_azithromycin334270.2638.66334270.2638.66--
J01DC02_cefuroxime876390.2528.92627280.2128.92249110.589.54
J01MB02_nalidixic acid5050.251.835050.251.83--
J01FA01_erythromycin157100.2082.00157100.2082.00--
J01FF02_lincomycin210.171.67110.161.00110.271.00
J01GA01_streptomycin110.161.00--110.161.00
J01GB03_gentamicin8890.152.24--8890.152.24
J01EA01_trimethoprim165230.1270.00165230.1270.00--
J01FA06_roxithromycin87140.1117.1487140.1117.14--
J01CA04_amoxicillin413210.1126.52413210.1126.52--
J01AA07_tetracycline2290.041.762290.041.76--
J02AB02_ketoconazole320.031.19320.031.19--
J01CE10_benzathine phenoxymethylpenicillin8870.032.748870.032.74--
J01AA02_doxycycline83110.016.2583110.016.25--

No. Mfr.: number of manufactures; DDD: Defined daily dose.

Note: Number of samples per drug represents the total number of brands at different strengths procured by all bidders. Some brands may have different strengths and the price per DDD may vary for the same drug by the same manufacturer. For example, a 10 mL vial of caspofungin contains either 50 mg or 70 mg, therefore the cost per DDD will be different between 2 strengths. Additionally, the same strengths may have different prices in different provinces.

Fig 3

ABC analysis of the quantities of procured antibacterials (in DDD) and the price.

No. Mfr.: number of manufactures; DDD: Defined daily dose. Note: Number of samples per drug represents the total number of brands at different strengths procured by all bidders. Some brands may have different strengths and the price per DDD may vary for the same drug by the same manufacturer. For example, a 10 mL vial of caspofungin contains either 50 mg or 70 mg, therefore the cost per DDD will be different between 2 strengths. Additionally, the same strengths may have different prices in different provinces. By AWaRe categories, the average price per DDD of Reserve group antibacterials was the highest (US $15.63 per DDD), followed by the Watch group antibacterials (US $0.86 per DDD), and Access group antibacterial (US $0.4 per DDD). The average price of non-recommended/unclassified antibacterials was 11.7 per DDD. We present the price of antimicrobials (ATC 5th level) in Table 3. The three most expensive antimicrobials were caspofungin (J02AX04) (US $284.5 per DDD), doripenem (J01DH04) (US $85.3 per DDD) and tigecycline (J01AA12) (US $65.4 per DDD). There is a large variability in antimicrobial price per DDD range which is represented as a ratio of the highest to lowest price of antimicrobial per DDD (H/L ratio) from very high (H/L ratio up to 82 for oral formulation or 40.26 for parenteral formulation) or no discrepancy (H/L = 0) for the branded forms (Table 3). Twenty-seven of thirty-eight (71.3%) oral forms and 10/55 (18.2%) parenteral forms of antimicrobials had H/L ratios above 10. Whilst almost all (59/77, 76.6%) antibacterials for systemic use (ATC 5th level, chemical substance) were procured from both domestic and international manufacturers, 18 were procured from either international or domestic manufactures (Fig 4 and Table 4). 82.7% of antibacterials were supplied by domestic producers (67 companies, supplied 572,698,014 DDDs) whilst 212 international manufactures from 35 countries supplied the remainder (119,658,771 DDD). Antibacterials supplied by international manufacturers accounted for 54.5% of the total spent (US $261,754,116) and 17.3% of the total DDDs procured. Among 35 countries with pharmaceutical companies sharing the antibacterial market in Vietnam, India and Cyprus contributed the highest proportions of total DDDs, together supplying 8.4% of total antibacterial (58,142,107 DDDs) in all sites, corresponding to 48.6% of total foreign antibacterials (J01) procured (28.6% from India and 20.1% from Cyprus).
Fig 4

Number of antimicrobial manufacturers in Vietnam.

Table 4

Source of manufacturers for selected antibacterials.

Antibacterials procured from only domestics manufacturesnorfloxacin and tinidazole (J01RA13)
lomefloxacin (J01MA07)
streptomycin (J01GA01)
lincomycin (J01FF02)
ciprofloxacin and tinidazole (J01RA11)
ceftibuten (J01DD14)
tetracycline (J01AA07)
pefloxacin (J01MA03)
benzylpenicillin (J01CE01)
chloramphenicol (J01BA01)
nalidixic acid (J01MB02)
ticarcillin and beta lactamase inhibitor (J01CR03)
oxacillin (J01CF04)
gentamicin (J01GB03)
spiramycin and metronidazole (J01RA04)
Antibacterial procured from only international manufacturestigecycline (J01AA12)
ertapenem (J01DH03)
parenteral azithromycin (J01FA10)

Discussion

Our study represents the first effort to describe the use and price of antimicrobials in healthcare facilities in Vietnam, a country with a high burden of drug resistant infections. In a previous study of antibacterial sales in 76 countries between 2000 and 2015, Vietnam ranked 11th in antibacterial consumption per capita with 32 DDDs per 1,000 inhabitants per day [1]. However, the use of antimicrobials by ATC index and by the route of administration in public hospitals has not been published. Additionally, we found that the proportion of total medication expenditure represented by antibacterials was high—28.5% of the total expenditure for medications across study sites. The amendment of 2019 AWaRe classification has overcome some limitations of the previous version, especially failures to classify many of the most commonly used drugs. Using the 2017 AWaRe classification, 25.8% of DDD (178.658.638 DDD) procured in our dataset were unclassified, among which 78.5% were 2nd generation cephalosporins (J01DC), 13.4% were 1st generation cephalosporins (J01DB), 5.4% were macrolides (J01FA) and 2.7% were other substances. Similarly, a large proportion of unclassified antibacterials by the 2017 AWaRe system was also reported in other countries, for example 60.3% in a survey of prescriptions among hospitalised children in 56 countries in 2015 [26]. These limitations of the AWaRe classification system were acknowledged by the WHO Essential Medicines List Working Group as requiring further revision [27]. However, the 2019 amendment enables us to re-classify these ‘other’ antibacterials in our dataset as belonging to the Access group (14.3% of DDD number of unclassified antibacterial), Watch group (85% of DDD number of unclassified antibacterial) and non-recommended/unclassified group (0.72% of DDD number of unclassified antibacterial). We found that cephalosporins were the most commonly prescribed class of antibiotics in Vietnam. In healthcare sectors in Europe, studies report that the most common antibacterials were beta-lactams, penicillins (J01C) [28]. The difference in prescribing patterns may be due to differences in resistance or knowledge. Numerous studies have reported increased resistance in Vietnam compared to Europe [9, 28–30] and in China, where the resistant levels are similar to Vietnam, 3rd-generation cephalosporins were the most consumed antibacterial in hospitals [31]. In a systematic review of studies published between 1993 and 2013 about antimicrobial prescription in China (n = 67) and Vietnam (n = 29), the most important factor influencing irrational prescription in Vietnam was lack of knowledge and effective control and regulation mechanisms for drugs use, whilst in China it was financial incentive and lack of knowledge [32]. In the first surveillance report by WHO on antibacterial consumption in 65 countries during the period of 2016–2018, the Philippines was the only country from Southeast Asia providing data on national consumption of antimicrobials for community and hospital use using the IQVIA and import database [10]. In the Philippines, the most frequently consumed antibacterials were tetracyclines and penicillins with each contributing 30% of total consumption of antibacterials (in DDD per 1000 inhabitants per day). This study provides important data concerning prices of antimicrobials used in Vietnam. A small number of antimicrobials accounted for a disproportionately large high expenditure. Carbapenems were only a small number of antimicrobials prescribed according to DDD, but a significant proportion of the total spend. Data on the national expenditure on antimicrobials is often limited and there are few data from other countries for comparison but it is likely that the situation of last resort antibacterials is similar in other setting. For example, in the US in 2015, the antibacterial expenditures were largest for daptomycin (1.3 billion or 14.7% of total expenditure), and although no data are provided on daptomycin usage, it is likely to be relatively infrequently used. With a total of 290 manufacturers sharing the antimicrobial market in Vietnam, currently, there are numerous manufacturers with different forms and formulation of antimicrobials on the Vietnamese market. For example, there were eight US Food and Drug Administration–approved manufacturers for Cefuroxime 250 mg tablet in US [33] whilst there were 20 manufacturers approved by the Vietnamese government for the same formulation and strength in Vietnam. This large number of domestic and international manufacturers likely leads to increased complexity in ensuring the quality of medications and regulating their manufacture and distribution. Additionally, for the most common class of antibacterials (second generation cephalosporins), we found that there were 6 drugs used in Vietnam, comparatively high compared to other countries. For example there are only 2 second generation cephalosporins licensed in the UK [34]. The larger number of drugs used in Vietnam may lead to difficulties for clinicians and pharmacists in gaining familiarity with individual drugs and also increases the burden on the government to ensure the quality of the additional number of preparations. This study has shown high variability in antimicrobial prices. Measurement of price and availability of antimicrobials is essential to inform policies about accessibility and affordability to the population. In a survey of the prices, availability, and affordability of 42 core medicines (including eight antibacterial substances) in 5 provinces in Vietnam in 2005, the prices of innovator drugs and the lowest priced generic drugs were 47 times and 11 times higher than the international reference prices (MSH), respectively [35]. The medicine prices in the public sectors were higher than in private sectors [35]. The reasons for this are unclear. In a qualitative study on the price of medication in Vietnam in 2008, the higher prices in public hospitals were suggested to be related to the high bed occupancy rates resulting in a reduced need to attract more patients through competitive pricing, or prices inflated up to 60% by commissions to prescribers and hospital pharmaceutical departments [36]. However, others have shown financial incentives may be not an important factor influencing doctor’s prescribing decision in Vietnam [32]. The International Medical Products Price Guide by Management Sciences for Health (MSH) is recommended as a most useful reference for medicine prices [37] and the 2015 version is the latest [24]. Among antibacterials in the Reserve group, the high/low ratio of cefepime according to MSH 2015 (4.39) was much lower than the one in this study (19.53) [24]. However, no data for other antibacterials in the Reserve group were available for cross reference. The pharmaceutical market in Vietnam is import-reliant and was estimated to reach US $5.2 billion in 2017 [25]. Ninety percent of the country’s medication expenditure was on imported medicines [38]. The European Union was the most important pharmaceutical manufacturer providing medications to Vietnam with a value of US $1.1 billion or 51% of Vietnam’s total pharmaceutical imports in 2014, in which France, Germany, Italy shares US $579 million or 73% of total pharmaceutical imports from the EU [39]. We confirmed that European countries were the leading exporters to Vietnam in term of spending on antibacterials whilst Asian countries (mainly India) accounted for the largest quantities. However, the majority of antimicrobial consumption was met by domestic manufacturers. This increase in national production is part of strategic plan for developing the Vietnam pharmaceutical industry by 2020 as the government set objectives to produce 80% of total annual medication consumption in the country [40]. Our study has some limitations. Firstly, we were unable to obtain data from all healthcare institutions in Vietnam due to bids being unpublished or published elsewhere, e.g. an institutional website. Based on the previous estimation of national drug expenditure (US $ 5.85 billion), we estimated our data represents at least 28.7% but this may be an underestimate because our dataset excluded nationally procured medications (antiretrovirals, anti-tuberculosis drug and anti-malarials). Secondly, we excluded the available tender-winning results of US $ 776,271,465 (equal to 13.4% of estimated national drug expenditure) from 47/75 tertiary hospitals because most of them were highly specialised hospitals and their pattern of antimicrobials use was driven by the specialities and different from general hospitals. This may lead to an under-representation of tertiary hospitals in our analysis and a corresponding underestimation of the contribution of Reserve group antibacterials. Furthermore the data used in the study may not be complete because hospitals may have extra calls for bids or not use all of the antibacterials purchased from these bids. However, the successful bids were based on the previous year’s actual (total) consumption and the institutions were required to use at least 80% of antimicrobials purchased in these bids, therefore our estimate is likely to be a reasonable estimate of use. Our data on antimicrobial usage in hospitals may be biased and underestimate exact usage because medications for hospitalised patients can also be purchased directly by patients, especially in primary and secondary hospitals, partly due to the fact that many Watch and Reserve antibacterials are not reimbursed by the national insurance programme and are consequently not available in hospital pharmacies [41]. We have no data to estimate this, but we consider this proportion to be small. In a prospective study of 892 hospitalised trauma patients admitted to a secondary hospital in Vietnam in 2010, the total medical care out-of-pocket cost paid by patients was US $270.6, 23% of this relating to drugs [42]. However, the out-of-pocket cost for antimicrobials in hospitalised patients was not specified. Additionally, there is some uncertainty about the number of hospitals included in this study as the bid by DoH covered the tenders of different public hospitals in the province and the number and nature of hospitals joining these provincial bids was unidentifiable. As electronic health records are currently being implemented in Vietnamese hospitals, it may be possible to obtain more accurate data in future, and to cross reference purchased drugs with prescribed drugs. A final limitation of this study is that we did not include private sector consumption. As the Vietnamese Government launched a strategy to increase the share of private hospital beds to 20% by 2020 [43], the growth of the private healthcare system may contribute significantly to consumption of antimicrobials.

Conclusions

Antimicrobials accounted for one third of the total spent on medications in study hospitals in Vietnam. The pattern of antibacterial consumption by AWaRe categories was similar to other countries. However, given the relatively high proportion of antimicrobial drug resistance in Vietnam and that although stewardship is important in reducing it, there is necessity for access in certain circumstances to AWARE reserve antibiotics. The optimal approach would be strict stewardship combined with price control, to allow access when needed and prevent access when not needed.

List of available antimicrobials.

(DOCX) Click here for additional data file. (JPG) Click here for additional data file. 23 Jul 2020 PONE-D-20-18659 Price and use of antimicrobials in the hospital sector of Vietnam, a lower middle-income country with an emerging pharmaceuticals market PLOS ONE Dear Dr. Dat, 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 when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This is an important paper, as there is data on consumption of antibiotics is still relatively scarce, and this is rarely linked to price. The fact that pharmacy and tertiary hospital data means that this is a partial picture, but this paper nevertheless provides a useful contribution to an important issue. The fact that antibiotics are more than a quarter of the total medicines budget for Vietnam is an important finding. This level of investment is sometimes surprising to policy makers and should encourage them to take antibiotic policies much more seriously. The fact that the proportionate expenditure on reserve antibiotics that are imported, is so high is another policy relevant finding. This study highlights an area where implementation of good public health and prescribing policies could save money and support a shift towards more domestically produced medicines. The conclusions are slightly surprising. The study has shown significant use and expenditure on Reserve antibiotics and that are not recommended by WHO. The authors conclusion is that there should be price controls on these groups. It is not clear why, as currently financial incentives align with good public health policy. The case could be made much more strongly that good stewardship programmes, that might shift consumption towards access groups are likely to result in significant cost savings, and support consumption of domestically produced medicines . This argument would increase the relevance of the study to policy makers and the broader policy debates on antibiotic stewardship, and might stimulate investement in stewardship programmes Most readers won’t be familiar with the Vietnamese health financing system and in particular whether there are financial incentives for practitioners or to hospitals to prescribe antibiotics. It would be helpful if the authors explained whether reimbursement is linked to either the costs of volumes of drugs that are prescribed (as happens in some Asian countries) Inclusion of antifungals is helpful, and the fact that the consumption in an emerging economy (with relatively low HIV) is relatively low is useful information. Given that the sample did not include many of the tertiary hospitals total consumption of these products may be even higher. Strengthening stewardship programmes to bring prescribing pr IN the introduction paragraph the authors should note that data quality on consumption patterns is still relatively poor, and so any rankings are questionable .. The statement that low and middle income countries are disproportionately responsible for the global growth in antibiotics is disingenuous, given that the burden of disease is higher in many of these countries, and their consumption of antibiotics was at a relatively low level. The authors imply in the discussion that the high use of cephalosporins in Chinaa nd Vietnam is because of resistance levels. Prescribing habits and culture may be a stronger driver (such as elevated concerns about allergy in China) The points about the fragmentation of the market and proliferation of products leading to high transaction costs for government and difficulties for clinicians are important and well made The authors state that the study does not include drugs purchased in pharmacies, and that there may be significant additional purchases of medicines by patients in primary and secondary care. It is difficult for readers not familiar with the health service utilization patterns to understand how big this contribution might be, and it would be helpful if the authors could offer some idea. Are there studies of service utilization or health expenditures which might provide some evidence??, Reviewer #2: A well conducted and interesting study looking at the antimicrobial resistance with a focus on pricing. However the following need to be looked at: 1. The title has to be modified as it does not really relate to patient purchase price as mostly observed in these type of studies. 2. Sentence on line number 6 in the introduction section has to be reformulated as it is not clear. (Overall antibiotic consumption (in DDDs per 1 000 population per day) differs 3 fold between countries .......) 3. In the first paragraph of Study approach: What is the role of provincial health authorities in medicine supply? Why were they purchasing medicines? is it for local use or for which types of facilities? 4. in the section of "Estimation of antimicrobial procurement and the cost of antimicrobials" first paragraph. Is the WHO recommendations similar to Vietnam's standard treatment guidelines? if not, an explanation on the variation with local treatment and why choice of WHO standards should be provided. 5. In the results section, paragraph 1. Does the budget for medication include medical supplies (e.g. gloves, cotton woo, spirit etc)? 6. Table 1, Column 3: what percentage of health facilities was being served by these 52 units included in the study? 7. On the antimicrobial medicines deemed not part of AWaRe, e.g. Nalidixic Acid, are these antibacterials not recommended in Vietnam through standard treatment guidelines?If they are recommended as part of standard treatment guidelines, then an explanation to that effect will be ideal. 8. Table 2 and in the text: List of drugs in each category should be provided as a supplementary table. The reason being that one can not know what is in J01CR, J01EA..etc... If others have to compare with the study the list of those medicines would be ideal 9. Figure 3. The cumulative values should be taken out of it and formulate it into separate graph as there is obscurity of the contributions of primary and secondary health facility in the graph 10. Table 3. For column 2, it will be better to specify how many samples were there per drug not only manufacturer. If the facilities purchased medicine manufactured by the same company but with different prices, it will make sense with various ratios observed in column 4. An example is J02AX04_caspofungin which has ratio of 1.10 even though the manufacturer supplying the medicine to Vietnam is just one. 11. In the discussion, the results in table 3 (column 4) does not relate to comparison with MSH reference price, therefore direct comparison with it as MPR may not be in the best interest. Either, in table 3 recalculate and change the 'High to Low ratio' to Median Price Ratio (MPR) for easy comparison. 12. There is a need for consistency in the use of the following words: 'antibacterials', 'antibiotics' and 'antimicrobials' Otherwise, the paper is providing a fair way of assessing antimicrobial consumption. Reviewer #3: This is an original work on costs of antibiotics in Vietnam. Interesting research has been performed, but the current manuscript needs clarity. GENERAL COMMENTS English needs to be revised. Bibliographic references are not accurate or missing. Please, verify their correspondence in the text and the standard required by the journal. Tables are dense, difficult to understand. Figures are pixeled. Pages nor lines are not numbered which complicates the revision. SPECIFIC COMMENTS Title Too large Introduction What is the objective of the study? The definition of the acronym LMIC is mentioned twice. There is an important focus on the AWaRe classification but the importance of using it to categorize the costs is not clear. There are confusion when using the terms expenditure, costs and price of drugs. Please harmonize the terms cost/price and specify from which perspective the expenditure is being measured. Methods There is substantial need for clarifying the Methods section. Several concepts are showed in the results/discussion, such as the pharmaceutical market in Vietnam, the different manufacturers/providers of the healthcare system and the relation with neighbour countries. -Study approach Please clarify why 52 provincial health authorities were chosen? They represent 2/3 of the data sources and may need different analysis as showed in the graphs. What are there relation with hospitals? Do they procure drugs for regional hospitals? Please explain. What does a health facility represent in Vietnam? Please explain. Why to choose public instead of private hospitals? The explanation comes too late in the Discussion/Limits. How were the hospitals chosen? Was it randomly? How did you have access to the “successful tenders”? Normally, these are confidential data and not publicly available. Please clarify. -Patient and Public Involvement This section is not necessary, as your data sources were obtained in the “successful tenders”. Results Reference 22 is a BMI document published in 2016. Please verify coherence with the text. Tab 1: Does “other medications” mean all other class of drugs present in the tender ? Tab 2 is mentioned twice in the text. Fig 2: what do you mean by “cost shares”? Parenteral formulations and oral formulations have obviously different costs. Why to present a graph? Please explain Fig 3: what does the cumulative budget represents? Are the drugs bought by the same payer (via different hospitals/provincial health authorities)? Tab 3: Not readable without the text, please synthesize (3 pages!), and add legend in the end of the table. By the end of the results there are information regarding manufacturers. This is an interesting focus that should be better explored and previously specified in the Methods section. Discussion The description of the use of antibiotics is not clear. Is it about the DDD calculated and indicated in the successful tenders? Are the facilities chosen representative for the rest of the country? Are they in the same region? Are there social/financial differences in terms of possibility to buy drugs outside the hospital (as mentioned in the text)? Please check duplicated information in the Introduction and Discussion sections. Further comparison with southeast countries would be more pertinent than with European countries, specially regarding pharma marketing. Why IQVIA is mentioned? Would you suggest why the private sector has lowest prices than the public sector? Hence it would be interesting to explain the reasons to choose to work with the public and not both private and public sectors. In the Limits section there are several information that should be earlier mentioned, notably in the Methods section. Conclusion “Antimicrobials accounted for a third of budget for medication in public hospitals in Vietnam.” This sentence is very ambitious as no representativeness of data analysed was discussed. The relation between the consumption of “Reserve and non-recommended” antibiotics and the need of a stewardship is not clear. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Elizabeth Tayler Reviewer #2: No Reviewer #3: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. 25 Sep 2020 Dear Editor, On behalf of all authors, I would like to express my sincere appreciation for your careful consideration and your very helpful comments to improve our manuscript. Please find below our response, with contributions from the entire research team, shown in red, for your review and consideration. We believe that we have addressed all your suggestions and comments, but please advise us if you consider our manuscript should be further improved. Your sincerely Vu Quoc Dat Reviewer #1: This is an important paper, as there is data on consumption of antibiotics is still relatively scarce, and this is rarely linked to price. The fact that pharmacy and tertiary hospital data means that this is a partial picture, but this paper nevertheless provides a useful contribution to an important issue. The fact that antibiotics are more than a quarter of the total medicines budget for Vietnam is an important finding. This level of investment is sometimes surprising to policy makers and should encourage them to take antibiotic policies much more seriously. The fact that the proportionate expenditure on reserve antibiotics that are imported, is so high is another policy relevant finding. This study highlights an area where implementation of good public health and prescribing policies could save money and support a shift towards more domestically produced medicines. The conclusions are slightly surprising. The study has shown significant use and expenditure on Reserve antibiotics and that are not recommended by WHO. The authors conclusion is that there should be price controls on these groups. It is not clear why, as currently financial incentives align with good public health policy. The case could be made much more strongly that good stewardship programmes, that might shift consumption towards access groups are likely to result in significant cost savings, and support consumption of domestically produced medicines . This argument would increase the relevance of the study to policy makers and the broader policy debates on antibiotic stewardship, and might stimulate investement in stewardship programmes [Author's Response To Reviewer Comments] We have revised the abstract and conclusion to explain that there is a large amount of necessary reserve group use in Vietnamese hospitals, due to the high levels of antibiotic resistance in the country. Thus, there is a need to facilitate reserve group use where it is needed but disincentivise reserve use where it is not. “Antimicrobials accounted for one third of the total spent on medications in study hospitals in Vietnam. The pattern of antibacterial consumption by AWaRe categories was similar to other countries. However, given the relatively high proportion of antimicrobial drug resistance in Vietnam and that although stewardship is important in reducing it, there is necessity for access in certain circumstances to AWARE reserve antibiotics. The optimal approach would be strict stewardship combined with price control, to allow access when needed and prevent access when not needed”. We also have added information of current antimicrobial resistance in Vietnam in introduction section: “Vietnam has one of the highest rates of antimicrobial drug resistance in Asia. In an antimicrobial resistance surveillance network of 16 hospitals in Vietnam between 2012 and 2013, the proportion of antimicrobial resistance was high among all pathogens isolated from clinical specimens: penicillin non-susceptible Streptococcus pneumoniae (67%, 229/344 isolates), methicillin-resistant Staphylococcus aureus (MRSA) (69%, 1098/1580 isolates), third-generation cephalosporin-resistant Escherichia coli (56%, 2342/4192 isolates) and Klebsiella pneumoniae (66%, 1479/2227 isolates), carbapenem-resistant Pseudomonas aeruginosa (33%, 578/1765 isolates) and carbapenem-resistant Acinetobacter spp. (70%, 1495/2138 isolates)”. Most readers won’t be familiar with the Vietnamese health financing system and in particular whether there are financial incentives for practitioners or to hospitals to prescribe antibiotics. It would be helpful if the authors explained whether reimbursement is linked to either the costs of volumes of drugs that are prescribed (as happens in some Asian countries) [Author's Response To Reviewer Comments] We have added discussion on the reason for higher prices in public hospitals and commission to prescribers. “The reasons for this are unclear. In a qualitative study on the price of medication in Vietnam in 2008, the higher prices in public hospitals were suggested to be related to the high bed occupancy rates resulting in a reduced need to attract more patients through competitive pricing, or prices inflated up to 60% by commissions to prescribers and hospital pharmaceutical departments (https://pubmed.ncbi.nlm.nih.gov/28453716/). However, others have shown financial incentives may be not an important factor influencing doctor’s prescribing decision in Vietnam (https://www.ncbi.nlm.nih.gov/pubmed/25793497).” Inclusion of antifungals is helpful, and the fact that the consumption in an emerging economy (with relatively low HIV) is relatively low is useful information. Given that the sample did not include many of the tertiary hospitals total consumption of these products may be even higher. Strengthening stewardship programmes to bring prescribing pr IN the introduction paragraph the authors should note that data quality on consumption patterns is still relatively poor, and so any rankings are questionable .. [Author's Response To Reviewer Comments] We have added this note in the introduction session as advised: “However, due to lack of resources for collecting reliable data and maintaining surveillance system, data on antibacterial consumption from LMICs are still limited and of poor quality, especially for countries from Southeast Asia” We were unsure whether the above sentence was complete, it seemed some words were missing in the sentence starting with “Strengthening…” We may therefore not have addressed this comment fully. The statement that low and middle income countries are disproportionately responsible for the global growth in antibiotics is disingenuous, given that the burden of disease is higher in many of these countries, and their consumption of antibiotics was at a relatively low level. [Author's Response To Reviewer Comments] It was suggested by Klein’s work (www.pnas.org/cgi/doi/10.1073/pnas.1717295115). We have revised the below sentences for clarity: “Antibacterial consumption was positively correlated with growth in per capita gross domestic product (GDP) and low- and middle-income countries (LMICs) are consequently responsible for driving the rise in global antibacterial consumption.” The authors imply in the discussion that the high use of cephalosporins in China and Vietnam is because of resistance levels. Prescribing habits and culture may be a stronger driver (such as elevated concerns about allergy in China) [Author's Response To Reviewer Comments] We found a systematic review on Irrational Use of Medicines in China and Vietnam (https://doi.org/10.1371/journal.pone.0117710), it shows that the most important factor influencing prescription of irrational medications in Vietnam was lack of knowledge, followed by lack of effective control and regulation mechanisms for drug use whilst it was financial incentives and lack of knowledge in China. We have revised and added the text in the Discussion section as below: “We found that cephalosporins were the most commonly prescribed class of antibiotics in Vietnam. In healthcare sectors in Europe, studies report that the most common antibacterials were beta-lactams, penicillins (J01C). The difference in presecribing patterns may be due to differences in resistance or knowledge. NUMEROUS STUDIES HAVE REPORTED INCREASED RESISTANCE IN VIETNAM COMPRED TO EUORPE [refs] AND whilst in China, where the resistant levels are similar to Vietnam, 3rd-generation cephalosporins were the most consumed antibacterial in hospitals. In a systematic review of studies published between 1993 and 2013 about antimicrobial prescription in China (n=67) and Vietnam (n=29) , the most important factor influencing irrational prescription in Vietnam was lack of knowledge and effective control and regulation mechanisms for drugs use, whilst in China it was financial incentive and lack of knowledge.” The points about the fragmentation of the market and proliferation of products leading to high transaction costs for government and difficulties for clinicians are important and well made The authors state that the study does not include drugs purchased in pharmacies, and that there may be significant additional purchases of medicines by patients in primary and secondary care. It is difficult for readers not familiar with the health service utilization patterns to understand how big this contribution might be, and it would be helpful if the authors could offer some idea. Are there studies of service utilization or health expenditures which might provide some evidence??, [Author's Response To Reviewer Comments] There are only few studies on service utilization describing this. Whilst there is undoubtedly widespread over-the-counter antimicrobial purchasing in Vietnam, the use of these for hospitalized patients is, from our experience, relatively limited. We have added the below in the discussion: “We have no data to estimate this, but we consider this proportion to be small. In a prospective study of 892 hospitalised trauma patients admitted to a secondary hospital in Vietnam in 2010, the total medical care out-of-pocket cost paid by patients was US $270.6, 23% of this relating to drugs. However, the out-of-pocket cost for antimicrobials in hospitalised patients was not specified”. Reviewer #2: A well conducted and interesting study looking at the antimicrobial resistance with a focus on pricing. However the following need to be looked at: 1. The title has to be modified as it does not really relate to patient purchase price as mostly observed in these type of studies. [Author's Response To Reviewer Comments] We have revised the title as “Purchase and use of antimicrobials in the hospital sector of Vietnam, a lower middle-income country with an emerging pharmaceuticals market” 2. Sentence on line number 6 in the introduction section has to be reformulated as it is not clear. (Overall antibiotic consumption (in DDDs per 1 000 population per day) differs 3 fold between countries .......) [Author's Response To Reviewer Comments] We have reworded the text for clarity as follows: “The difference in overall antibacterial consumption between the highest and lowest -consuming countries was 3-fold for total use (in DDDs per 1 000 population per day), and up to 16 fold in volume for quinolones and cephalosporins among the mostly high-income countries in the Organisation for Economic Co-operation and Development (OECD)” 3. In the first paragraph of Study approach: What is the role of provincial health authorities in medicine supply? Why were they purchasing medicines? is it for local use or for which types of facilities? [Author's Response To Reviewer Comments] We have added explanation in the methods section: “The current medication procurement in Vietnam is mostly implemented through bidding which uses a decentralised (individual hospitals directly conduct the procurement) or centralised model (at national level by ministry of health or at provincial level by provincial departments of health, DoHs). At provincial level, centralised procurement involves provincial DoHs gathering procurement needs of provincial and districts hospitals under their jurisdiction, calling for, reviewing and accepting bids. Hospitals’ estimated requirements for antibacterials are based on consumption in the previous year. Payment is made by the hospitals regardless of whether a decentralised or centralised bid model was used.” 4. in the section of "Estimation of antimicrobial procurement and the cost of antimicrobials" first paragraph. Is the WHO recommendations similar to Vietnam's standard treatment guidelines? if not, an explanation on the variation with local treatment and why choice of WHO standards should be provided. [Author's Response To Reviewer Comments] We have added the below text in that section: “Currently, there are no national stewardship programmes defining access to different antimicrobials but individual hospitals may have their own policies on their use”. 5. In the results section, paragraph 1. Does the budget for medication include medical supplies (e.g. gloves, cotton woo, spirit etc)? [Author's Response To Reviewer Comments] No, it does not include medical supplies or medical equipment. We added text for clarity. “We included tender-winning results totalling US $1.68 billion from 23 secondary hospitals, 7 primary hospitals and 52 provincial departments of health in Vietnam. This excludes disposable and consumable medical supplies and medical equipment” 6. Table 1, Column 3: what percentage of health facilities was being served by these 52 units included in the study? [Author's Response To Reviewer Comments] We have added explanation of the role of Departments of Health in the methods. Because the DoH gathered bid information from the provincial and district hospitals under their jurisdiction without details of buyers, we can’t provide the exact percentage of health facilities. This was discussed as a limitation in that part of the discussion. However, based on the forecasted estimation of national budget for medication, we estimate that our analysis represents 28.7% of the national budget or medication. 7. On the antimicrobial medicines deemed not part of AWaRe, e.g. Nalidixic Acid, are these antibacterials not recommended in Vietnam through standard treatment guidelines? If they are recommended as part of standard treatment guidelines, then an explanation to that effect will be ideal. [Author's Response To Reviewer Comments] We found 4 antibacterials that were purchased and used in Vietnam, but were unclassified by the 2019 AWaRe classification (ticarcillin with a beta-lactamase inhibitor, nalidixic acid, norfloxacin and tinidazole). These are still recommended by national treatment guidelines for specific infections. We have revised these drugs as unclassified throughout the manuscript for clarity and distinguished them from not-recommended drugs by AWaRe. “We identified 4 antibacterials that were unclassified by the 2019 AWaRe classification (ticarcillin with a beta-lactamase inhibitor (J01CR03), nalidixic acid (J01MB02), norfloxacin and tinidazole (J01RA13) and tinidazole (J01XD02)) but remain recommended by national treatment guidelines for specific infections” 8. Table 2 and in the text: List of drugs in each category should be provided as a supplementary table. The reason being that one can not know what is in J01CR, J01EA..etc... If others have to compare with the study the list of those medicines would be ideal [Author's Response To Reviewer Comments] We have added a full list of available drugs by category as a supplementary table (Supplementary table 1. List of available antimicrobials) as advised. 9. Figure 3. The cumulative values should be taken out of it and formulate it into separate graph as there is obscurity of the contributions of primary and secondary health facility in the graph [Author's Response To Reviewer Comments] We would like to keep the cumulative line as it is common in pareto analysis (ABC analysis) which can help to identify antimicrobials that are consuming large parts of the budget. We have added a reference (World Health Organization. (‎2018)‎. Methods to analyse medicine utilization and expenditure to support pharmaceutical policy implementation. World Health Organization. https://apps.who.int/iris/handle/10665/274282.). 10. Table 3. For column 2, it will be better to specify how many samples were there per drug not only manufacturer. If the facilities purchased medicine manufactured by the same company but with different prices, it will make sense with various ratios observed in column 4. An example is J02AX04_caspofungin which has ratio of 1.10 even though the manufacturer supplying the medicine to Vietnam is just one. [Author's Response To Reviewer Comments] We have added the number of samples per drug and added the below text under the table: “Number of samples per drug represents the total number of brands at different strengths procured by all bidders. Some brands may have different strengths and the cost per DDD may vary for the same drug by the same manufacturer. For example, a 10 mL vial of caspofungin contains either 50 mg or 70 mg, therefore the cost per DDD will be different between 2 strengths. Additionally, the same strengths may have different prices in different provinces”. 11. In the discussion, the results in table 3 (column 4) does not relate to comparison with MSH reference price, therefore direct comparison with it as MPR may not be in the best interest. Either, in table 3 recalculate and change the 'High to Low ratio' to Median Price Ratio (MPR) for easy comparison. [Author's Response To Reviewer Comments] In the MSH reference provided both High/Low ratio and Median Price Ratio (MPR), we intended to examine the variation between the highest unit price with the lowest unit price. In the discussion, we use the H/L ratio to compare the variation of price in our analysis and MSH reference. 12. There is a need for consistency in the use of the following words: 'antibacterials', 'antibiotics' and 'antimicrobials' [Author's Response To Reviewer Comments] We have replaced antibiotics by antibacterials. In our manuscript, antimicrobials refers to antibacterials and antifungals Otherwise, the paper is providing a fair way of assessing antimicrobial consumption. Reviewer #3: This is an original work on costs of antibiotics in Vietnam. Interesting research has been performed, but the current manuscript needs clarity. GENERAL COMMENTS English needs to be revised. [Author's Response To Reviewer Comments] We have proofread the manuscript. We are happy for the editorial team to make further changes to the English as they see fit. Bibliographic references are not accurate or missing. Please, verify their correspondence in the text and the standard required by the journal. [Author's Response To Reviewer Comments] We have updated bibliographies using Plos style. Tables are dense, difficult to understand. [Author's Response To Reviewer Comments] We recognised our tables are dense. We will change this table to a supplementary table if the editor agrees. Figures are pixeled. [Author's Response To Reviewer Comments] We have checked the quality of figures to meet the journal requirement. We think these figures were pixelated when they were saved as a pdf file. Pages nor lines are not numbered which complicates the revision. [Author's Response To Reviewer Comments] We have numbered lines as advised. SPECIFIC COMMENTS Title Too large [Author's Response To Reviewer Comments] We believe the title – with minor changes - reflects the contents of the manuscript appropriately, also the length is within the length prescribed by the journal Introduction What is the objective of the study? [Author's Response To Reviewer Comments] We have clarified our objective as follows “Our study reports the availability and price of antibacterials and estimates their usage in public hospitals in Vietnam” The definition of the acronym LMIC is mentioned twice. [Author's Response To Reviewer Comments] We have removed the duplicate. There is an important focus on the AWaRe classification but the importance of using it to categorize the costs is not clear. [Author's Response To Reviewer Comments] We have clarified the importance as follow: “Antimicrobials accounted for one third of the total spent on medications in study hospitals in Vietnam. The pattern of antibacterial consumption by AWaRe categories was similar to other countries. However, given the relatively high proportion of antimicrobial drug resistance in Vietnam and that although stewardship is important in reducing it, there is necessity for access in certain circumstances to AWARE reserve antibiotics. The optimal approach would be strict stewardship combined with price control, to allow access when needed and prevent access when not needed” There are confusion when using the terms expenditure, costs and price of drugs. Please harmonize the terms cost/price and specify from which perspective the expenditure is being measured. [Author's Response To Reviewer Comments] We have revised the term “prices” for the perspective of the health authorities and hospitals. We also clarified in the Study approach section “Payment is made by the hospitals regardless of whether a decentralised or centralised bid model was used” Methods There is substantial need for clarifying the Methods section. Several concepts are showed in the results/discussion, such as the pharmaceutical market in Vietnam, the different manufacturers/providers of the healthcare system and the relation with neighbour countries. -Study approach Please clarify why 52 provincial health authorities were chosen? They represent 2/3 of the data sources and may need different analysis as showed in the graphs. What are there relation with hospitals? Do they procure drugs for regional hospitals? Please explain. What does a health facility represent in Vietnam? Please explain. [Author's Response To Reviewer Comments] We included 52 provincial departments of health because of the availability of their data. We have added further explanation about this in the Methods section “The current medication procurement in Vietnam is mostly implemented through bidding which uses a decentralised (individual hospitals directly conduct the procurement) or centralised model (at national level by ministry of health or at provincial level by provincial departments of health, DoHs). At provincial level, centralised procurement involves provincial DoHs gathering procurement needs of provincial and districts hospitals under their jurisdiction, calling for, reviewing and accepting bids. Hospitals’ estimated requirements for antibacterials are based on consumption in the previous year. Payment is made by the hospitals regardless of whether a decentralised or centralised bid model was used.” The representativeness of data was indirectly estimated through the national drug expenditure as described in the limitations section in Discussion. Why to choose public instead of private hospitals? The explanation comes too late in the Discussion/Limits. [Author's Response To Reviewer Comments] We choose public heath facilities because of the data availability and we recognized it is a limitation of the study. Additionally, the private hospitals accounted for only 5% of total hospital beds. We have updated below information in the study setting. “In the private sector, there were 231 private hospitals with 16,000 beds (approximately 5% of national hospital beds) in the country by 2019” How were the hospitals chosen? Was it randomly? How did you have access to the “successful tenders”? Normally, these are confidential data and not publicly available. Please clarify. [Author's Response To Reviewer Comments] We have added explanations for the reason to choose hospitals in the Data resources section as advised: “All successful bids with available data were used for this analysis”. We described in the Methods section that the data was collected from the Drug Administration of Vietnam (DAV) which is the MoH regulatory authority for pharmaceutical products in Vietnam. As requested by the government, this information is public. We have clarified the role of DAV as the MoH regulatory authority. “Data on the price and characteristics of procured antimicrobials in Vietnam were taken from the successful tenders for medicines in 2018 for hospitals and provincial DoHs in Vietnam as published on the website of the Drug Administration of Vietnam which is the Ministry of Health regulatory authority” -Patient and Public Involvement This section is not necessary, as your data sources were obtained in the “successful tenders”. [Author's Response To Reviewer Comments] We have removed this part. Results Reference 22 is a BMI document published in 2016. Please verify coherence with the text. [Author's Response To Reviewer Comments] We couldn’t find the actual data for the pharmaceutical sales in Vietnam in 2018, therefore we used the forecasted estimation from the BMI documents from 2016. Tab 1: Does “other medications” mean all other class of drugs present in the tender ? [Author's Response To Reviewer Comments] Yes, it represents all other classes of drug (non-antimicrobials). We have clarified in table 1. Tab 2 is mentioned twice in the text. [Author's Response To Reviewer Comments] We have removed the duplicate. Fig 2: what do you mean by “cost shares”? Parenteral formulations and oral formulations have obviously different costs. Why to present a graph? Please explain [Author's Response To Reviewer Comments] We have changed to “proportion of bidding price”. Fig 3: what does the cumulative budget represents? Are the drugs bought by the same payer (via different hospitals/provincial health authorities)? [Author's Response To Reviewer Comments] Cumulative budget represents cumulative percentage of budget for antimicrobials as shown by the secondary horizontal axis on the right. Tab 3: Not readable without the text, please synthesize (3 pages!), and add legend in the end of the table. [Author's Response To Reviewer Comments] We will change this table to a supplementary table if the editor agrees. We have added table legends and abbreviations. By the end of the results there are information regarding manufacturers. This is an interesting focus that should be better explored and previously specified in the Methods section. [Author's Response To Reviewer Comments] We have added the below text in the “Materials and Methods”, under “Data resources” sections. “We described the antimicrobial manufacturers by their country of origin to estimate the market shares between domestic and international manufacturers which may provide some insight into manufacturing capacity” Discussion The description of the use of antibiotics is not clear. Is it about the DDD calculated and indicated in the successful tenders? [Author's Response To Reviewer Comments] We have used DDD from successful tenders as a proxy for use. Are the facilities chosen representative for the rest of the country? Are they in the same region? Are there social/financial differences in terms of possibility to buy drugs outside the hospital (as mentioned in the text)? [Author's Response To Reviewer Comments] We have added a supplementary figure for the data origins, we believe these are representative for the entire country. Supplementary figure 1. Mapping of data origins. Please check duplicated information in the Introduction and Discussion sections. [Author's Response To Reviewer Comments] We have removed the duplicated paragraph in the Introduction. Further comparison with southeast countries would be more pertinent than with European countries, specially regarding pharma marketing. [Author's Response To Reviewer Comments] We recognise the comparison with Southeast Asia and other countries with the same income level is important but there is very limited data from these regions. Why IQVIA is mentioned? [Author's Response To Reviewer Comments] It was mentioned as a source of data used in the WHO report. We tried to provide readers with a context of data sources and we declared to have no conflict of interest. Would you suggest why the private sector has lowest prices than the public sector? Hence it would be interesting to explain the reasons to choose to work with the public and not both private and public sectors. [Author's Response To Reviewer Comments] We chose the public sectors for our analysis due to the availability of data. We have added information to clarify the sampling and data collection. The fact that medication has lower price in the private sectors was observed in previous studies (Nguyen AT, Knight R, Mant A, Cao QM, Auton M. Medicine prices, availability, and affordability in Vietnam. Southern Med Review. 2009;2(2).). “The reasons for this are unclear. In a qualitative study on the price of medication in Vietnam in 2008, the higher prices in public hospitals were suggested to be related to the high bed occupancy rates, and lack of motivation to attract more patients through competitive pricing or prices inflated up to 60% by commissions to prescribers and hospital pharmaceutical departments (https://pubmed.ncbi.nlm.nih.gov/28453716/) . However, others have shown financial incentives may be not an important factor influencing doctor’s prescribing decision in Vietnam (https://www.ncbi.nlm.nih.gov/pubmed/25793497).” In the Limits section there are several information that should be earlier mentioned, notably in the Methods section. Conclusion “Antimicrobials accounted for a third of budget for medication in public hospitals in Vietnam.” This sentence is very ambitious as no representativeness of data analysed was discussed. The relation between the consumption of “Reserve and non-recommended” antibiotics and the need of a stewardship is not clear. [Author's Response To Reviewer Comments] We have revised the conclusion and removed the relation with antimicrobial stewardship. We hope the representativeness of data has been sufficiently clarified in the revised manuscript. “Antimicrobials accounted for one third of the total spent on medications in study hospitals in Vietnam. The pattern of antibacterial consumption by AWaRe categories was similar to other countries. However, given the relatively high proportion of antimicrobial drug resistance in Vietnam and that although stewardship is important in reducing it, there is necessity for access in certain circumstances to AWARE reserve antibiotics. The optimal approach would be strict stewardship combined with price control, to allow access when needed and prevent access when not needed.” Submitted filename: 2020 09 23 Response to Reviewers.docx Click here for additional data file. 5 Oct 2020 Purchase and use of antimicrobials in the hospital sector of Vietnam, a lower middle-income country with an emerging pharmaceuticals market PONE-D-20-18659R1 Dear Dr. Dat, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Khin Thet Wai, MBBS, MPH, MA (Population & Family Planning Resear Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ********** 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 #1: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know ********** 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 #1: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? 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 #1: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Elizabeth Tayler 9 Oct 2020 PONE-D-20-18659R1 Purchase and use of antimicrobials in the hospital sector of Vietnam, a lower middle-income country with an emerging pharmaceuticals market Dear Dr. Dat: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Khin Thet Wai Academic Editor PLOS ONE
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