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. 2021 Jan 20;16(1):e0241899. doi: 10.1371/journal.pone.0241899

High global consumption of potentially inappropriate fixed dose combination antibiotics: Analysis of data from 75 countries

Barbara Bortone 1, Charlotte Jackson 2, Yingfen Hsia 2,3,*, Julia Bielicki 2,4, Nicola Magrini 5, Mike Sharland 2
Editor: Iddya Karunasagar6
PMCID: PMC7817037  PMID: 33471786

Abstract

Antibiotic fixed dose combinations (FDCs) can have clinical advantages such as improving effectiveness and adherence to therapy. However, high use of potentially inappropriate FDCs has been reported, with implications for antimicrobial resistance (AMR) and toxicity. We used a pharmaceutical database, IQVIA-Multinational Integrated Data Analysis System (IQVIA-MIDAS®), to estimate sales of antibiotic FDCs from 75 countries in 2015. Antibiotic consumption was estimated using standard units (SU), defined by IQVIA as a single tablet, capsule, ampoule, vial or 5ml oral suspension. For each FDC antibiotic, the approval status was assessed by either registration with the United States Food and Drug Administration (US FDA) or inclusion on the World Health Organization (WHO) Essential Medicines List (EML). A total of 119 antibiotic FDCs were identified, contributing 16.7 x 109 SU, equalling 22% of total antibiotic consumption in 2015. The most sold antibiotic FDCs were amoxicillin-clavulanic acid followed by trimethoprim/sulfamethoxazole and ampicillin/cloxacillin. The category with the highest consumption volume was aminopenicillin/β-lactamase inhibitor +/- other agents. The majority of antibiotic FDCs (92%; 110/119) were not approved by the US FDA. Of these, the most sold were ampicillin/cloxacillin, cefixime/ofloxacin and metronidazole/spiramycin. More than 80% (98/119) of FDC antibiotics were not compatible with the 2017 WHO EML. The countries with the highest numbers of FDC antibiotics were India (80/119), China (25/119) and Vietnam (19/119). There is high consumption of FDC antibiotics globally, particularly in middle-income countries. The majority of FDC antibiotic were not approved by either US FDA or WHO EML. International initiatives such as clear guidance from the WHO EML on which FDCs are not appropriate may help to regulate the manufacturing and sales of these antibiotics.

Introduction

Global antibiotic consumption has been changing rapidly, increasing by 65% between 2000 and 2015, mainly in low- and middle-income countries (LMICs) [1,2]. Fixed dose combinations (FDCs) including one or more products with antibacterial activity have previously been noted as a concern, but there has been limited data on the scale of their use [3–6]. FDCs are defined by the World Health Organization (WHO) as “A combination of two or more actives in a fixed ratio of doses. This term is used generically to mean a particular combination of actives irrespective of the formulation or brand. It may be administered as single entity products given concurrently or as a finished pharmaceutical product” [7]. These products can have advantages such as improving treatment response compared to monotherapy, due to synergistic mechanisms (such as sulfamethoxazole/trimethoprim), or by increasing adherence to therapy.

FDCs are well-established in conditions such as tuberculosis, malaria and HIV treatment. However, the consumption of potentially clinically inappropriate antibiotic FDCs has been reported in some countries, raising concerns about the lack of proven efficacy, increasing toxicity or their potential effect on selecting for antimicrobial resistance (AMR) [4–6]. In 2017, the WHO Essential Medicines List (EML) Working Group classified antibiotics in the EML and EML for Children (EMLc) into three groups: Access, Watch, and Reserve (AWaRe classification). The Access group contains generally narrow spectrum antibiotics recommended as first and second choice for most common clinical infection syndromes. The Watch group contains broader spectrum antibiotic classes corresponding to the highest priority agents on the list of critically important antimicrobial drugs for human medicine. The Reserve group consists of last resort antibiotics for targeted use in multidrug resistant infections (Sharland et al., 2018). The new AWaRe classification is intended to be easy to apply to monitor antibiotic use and inform antibiotic stewardship. We therefore aimed to quantify the global consumption of antibiotic FDCs and to describe the types of combinations used. We also identified their approval status with the US Food and Drug Administration (FDA) and compatibility with the WHO’s 2017 revision of the Essential Medicines List (EML).

Methods

Data

This was an ecological study to assess the total sale of antibiotic FDCs. We estimated global antibiotic FDCs sales in 2015 using the IQVIA-Multinational Integrated Data Analysis System (IQVIA-MIDAS®) database. IQVIA-MIDAS is a commercial database containing data from pharmacy retails sales throughout the supply chains, including overall antibiotic volume sold to retailers and hospital pharmacies by wholesalers. The proportion of wholesalers contributing data to IQVIA-MIDAS varies between represented countries and IQVIA adjusts the reported data based on the market share of participating wholesalers, to provide estimates of total sales in the sectors represented in each country. Our dataset contains annual pharmaceutical sales data for 75 countries/regions. Central America (Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama) and Francophone West Africa (Benin, Burkina Faso, Cameroon, Chad, Côte d’Ivoire, Republic of Congo, Guinea, Mali, Niger, Senegal, and Togo) are defined as two regions with aggregated sales for these countries in the database [8].

Annual sales of each antibiotic (including information on component antibiotics, formulation, trade name and manufacturer) are recorded for each country. Antibiotic sales were expressed in standard units (SU), with 1 SU defined by IQVIA as one tablet, capsule or ampoule/vial or 5ml oral suspension. We did not include anti-tuberculosis drugs, antiviral drugs, and antifungal drugs in our analyses.

Analysis

We defined antibiotic FDCs as medications consisting of at least one Anatomical Therapeutic Chemical (ATC) code J01 systemic antibiotic with another J01 antibiotic or a β-lactamase inhibitor or a 5-nitroimidazole with or without any other medication (e.g probiotics, non-steroidal anti-inflammatory drugs). Antibiotic FDCs were aggregated in categories based on the WHO ATC Classification System [9]. Penicillins were classified as β-lactamase sensitive penicillins, β-lactamase resistant penicillins, aminopenicillins, ureidopenicillins and carboxypenicillins. Ureidopenicillins and carboxypenicillin were grouped as antipseudomonal penicillins [10]. The total annual sales of each antibiotic FDC sold was recorded by formulation type. For each antibiotic FDC, we summed the total consumption and reported the number of countries where it was sold. Total consumption for each antibiotic FDC was quantified by country income. The World Bank categories were used to classify countries as high income and low/middle income countries (HICs and LMICs) [11].

Approval status of antibiotic FDCs

Each of the antibiotic FDCs was categorised as approved or not approved by the US FDA by searching the FDA website [12]. For each country, the number and volume of antibiotic FDCs not approved by the FDA was expressed as a percentage of total antibiotic sales and total antibiotic FDCs.

Classification of antibiotic FDCs according to WHO criteria

Antibiotic FDCs were also assessed based on the WHO 2017 revision of EML [13]. EML compatible antibiotic FDCs were grouped into Access, Watch, and Reserve using the WHO AWaRe classification.

Antibiotic FDCs with two critically important antibiotics

The components of the antibiotic FDCs were also matched to the WHO’s “critically important antibiotics” (CIA) classification [14] to identify antibiotic FDCs in which both the components belonged to the “highest priority critically important antibiotics” group.

Results

A total of 74.4 x 109 SU of antibiotic agents was sold in 2015. Amongst these, 119 different antibiotic FDCs were identified (S1 Table), contributing to 16.7 x 109 SU, 22.5% of all antibiotic sales. The highest number of antibiotic FDCs were in the category of aminopenicillin/β-lactamase resistant penicillin (Table 1). The category with the greatest sales was that of aminopenicillin /β-lactamase inhibitor +/- other agents (Table 1).

Table 1. Categories of antibiotic Fixed Dose Combinations (FDCs).

FDC types Standard Unite sold Number of FDCs
Aminopenicillin /β-lactamase inhibitor //- other agents 8.60 x 109 8
Sulphonamides/trimethoprim+/- other agents 3.62 x 109 9
Aminopenicillin / β-lactamase resistant penicillin +/- other agents 1.54 x 109 21
Antipseudomonal penicillin /β-lactamase inhibitor 0.95 x 109 4
3rd-4th-5th gen. cephalosporins /β-lactamase inhibitor +/- other agents 0.55 x 109 15
Cephalosporins / fluoroquinolones 0.40 x 109 6
1st-2nd gen. cephalosporins / β-lactamase inhibitor +/- other agents 0.26 x 109 8
Macrolide/ 5-nitroimidazole 0.24 x 109 3
Macrolide/cephalosporin+/-other agents 0.21 x 109 3
Cephalosporin/ β-lactamase resistant penicillin +/- other agents 0.10 x 109 7
Cephalosporin/trimethoprim 0.09 x 109 2
Cephalosporin/oxazolidinone 0.04 x 109 2
Fluoroquinolone/ 5-nitroimidazole 0.04 x 109 8
Macrolide / fluoroquinolone +/- other agents 0.04 x 109 2
Cephalosporin/5-nitroimidazole 0.03 x 109 1
Other combinations 0.01 x 109 20
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Approximately one in six (20/119) antibiotic FDCs included probiotics as additional agents; probiotics were mostly Lactobacillus acidophilus and Bacillus coagulans. The most sold was cefixime/dicloxacillin/Lactobacillus acidophilus. The country with the highest number of antibiotic FDCs sold was India (80), followed by China (25) and Vietnam (19) (Fig 1). Overall, the most sold FDC by volume was amoxicillin/clavulanic acid (8.38 x 109 SU), followed by sulfamethoxazole/trimethoprim (3.61 x 109 SU) and ampicillin/cloxacillin (0.95 x 109 SU) (Table 2 and S1 Table). Amoxicillin/clavulanate and sulfamethoxazole/trimethoprim were sold by all 75 countries; other widely sold antibiotic FDCs were piperacillin/tazobactam (66) and ampicillin/sulbactam (49) (Table 2).

Fig 1. Number of fixed dose combination (FDC) antibiotic sold by country.

Fig 1

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Table 2. Top 10 list of most sold antibiotic FDCs and the number of countries they are sold in.

FDC Standard Unite sold Number of countries sold in
amoxicillin/clavulanic acid 8.38 x 109 75
sulfamethoxazole/trimethoprim 3.61 x 109 75
ampicillin/cloxacillin 0.95 x 109 13
piperacillin/tazobactam 0.79 x 109 66
cefixime/ofloxacin 0.31 x 109 1
metronidazole/spiramycin 0.24 x 109 17
cefpodoxime proxetil/clavulanic acid 0.23 x 109 3
amoxicillin/flucloxacillin 0.19 x 109 7
azithromycin/cefixime 0.17 x 109 2
cefoperazone/sulbactam 0.16 x 109 28
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Compared to other countries, India accounted for the greatest sales volume of amoxicillin/clavulanic acid, sulfamethoxazole/trimethoprim, and ampicillin/cloxacillin. There were clear country level differences in sales of FDCs, with the highest sales of piperacillin/tazobactam in Australia, metronidazole/spiramycin in France and cefoperazone/sulbactam in China.

FDA approval

Only 9/119 antibiotic FDCs were approved by the US FDA (7.5%) (Table 3). Of the 110 antibiotic FDCs not authorized by US FDA (92.5%), the highest numbers of combinations and the largest sales volumes were in the categories containing aminopenicillin+β-lactamase resistant penicillins +/- other agents (probiotics, lactic acid, serrapeptase) (19) and that including 3rd-4th-5th generation cephalosporins/β-lactamase resistant penicillins +/- other agents (13) (S2 Table).

Table 3. Antibiotic FDCs authorized by FDA and the number of countries they are sold in.

FDCs Standard Unite sold globally Number of countries sold in
amoxicillin/clavulanic acid 8.38 x 109 75
sulfamethoxazole/trimethoprim 3.61 x 109 75
piperacillin/tazobactam 0.79 x 109 66
ampicillin/sulbactam 0.12 x 109 49
clavulanic acid/ticarcillin 0.02 x 109 19
phenazopyridine/sulfamethoxazole/trimethoprim 0.02 x 108 1
ceftolozane/tazobactam 0.01 x 107 9
avibactam/ceftazidime 0.07 x 106 2
dalfopristin/quinupristin 0.02 x 106 3
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Overall, 53/75 (70.7%) countries sold at least one FDC not approved by the US FDA (Fig 1); 31/53 countries (58.4%) were LMIC. The highest number of “not FDA-approved” antibiotic FDCs were sold in India, China, Francophone West Africa and Vietnam (Fig 1). India and Francophone West Africa had the highest percentage of antibiotic FDCs not approved by the US FDA (93.8% of total antibiotic FDCs). Ampicillin/cloxacillin was the highest sold antibiotic FDC which was not FDA-approved, followed by cefixime/ofloxacin, and metronidazole/spiramycin (Table 4). A total of 3.81 x 109 SU of antibiotic FDCs not approved by the US FDA were sold, corresponding to 22.7% of the antibiotic FDCs SU sold and to 5.1% of the total antibiotic consumption, with considerable variation across countries (S3 Table).

Table 4. Antibiotic FDCs sold in the highest volumes in 2015 and not FDA approved FDCs and number of countries sold in.

FDC Standard Unite globally sold Number of countries sold in
ampicillin/cloxacillin 0.95 x 109 13
cefixime/ofloxacin 0.31 x 109 1
metronidazole/spiramycin 0.24 x 109 17
cefpodoxime proxetil/clavulanic acid 0.22 x 109 3
amoxicillin/flucloxacillin 0.19 x 109 7
azithromycin/cefixime 0.17 x 109 2
cefoperazone/sulbactam 0.16 x 109 28
amoxicillin/cloxacillin 0.16 x 109 4
cefixime/clavulanic acid 0.12 x 109 2
cefalexin/trimethoprim 0.09 x 109 1
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Compatibility of antibiotic FDCs with the WHO EML

Among the 119 antibiotic FDCs, 98 (82.3%) were not compatible with the 2017 WHO EML (S4 Table). Among the 21 WHO-compatible antibiotic FDCs (S3 Table), 2 belonged to the “Access” category (amoxicillin/clavulanic acid and sulfamethoxazole/trimethoprim), 16 were compatible with the “Watch” group and 3 with the “Reserve” group (S4 Table). Ten antibiotic FDCs included two highest priority critically important antibiotics (S5 Table). Of these, the largest consumption volumes were reported for cefixime/ofloxacin and azithromycin/cefixime; none of these 10 antibiotic FDCs were listed on the EML or approved by the US FDA.

Discussion

We have analysed sales data on antibiotic fixed dose combinations from 75 countries, adding to previous studies which used data from single countries or regions [4–6]. Overall, antibiotic FDCs represent a substantial proportion of all systemic antibiotic consumption, accounting for about 20% of systemic antibiotic SU sold in 2015. The majority of the antibiotic FDCs identified were not compatible with the EML and were not approved by the US FDA, and several antibiotic FDCs contained two agents classified by the WHO as highest priority critically important antibiotics.

Globally, the most sold antibiotic FDCs were amoxicillin/clavulanate and sulfamethoxazole/trimethoprim, which were sold in all countries and accounted for about 50% and 20% of the total antibiotic FDCs consumption, respectively. This is consistent with these drugs being recommended for treatment of common infectious conditions (such as acute otitis media, community acquired pneumonia and urinary tract infections) and with their inclusion on the EML as Access antibiotics [13]. However, there were many other widely used antibiotic FDCs, particularly from middle income countries, that were not on the EML. The category including the highest number of types of antibiotic FDCs was that of aminopenicillin/ β-lactamase resistant penicillins with or without probiotics followed by 3rd-4th-5th generation cephalosporins plus β-lactamase inhibitors with or without probiotics.

Defining clinically “inappropriate” antibiotic FDCs is complex and beyond the scope of this study. Previous studies have used as a standard of appropriateness the authorization status of antibiotic FDCs by the FDA, UK Medicines and Healthcare products Regulatory Agency (MHRA) and European Medicines Agency (EMA) and local drug regulatory organisations [4–6]. We only used the US FDA to evaluate approval status for marketed FDC antibiotics in this study, as US FDA regulation is a widely accepted benchmark for drug approvals globally, while the EMA has both centralised and devolved local regulations for drug approval processes.

However, countries with different health priorities to the US may investigate and approve drugs (including antibiotic FDCs) which have not been approved by the US FDA. Therefore, in some countries, the use of antibiotic FDCs not approved by the US FDA might be clinically appropriate (e.g. those including aminopenicillin/β-lactamase inhibitor, anti-pseudomonas penicillin / β-lactamase inhibitor or a third-fourth-fifth generation cephalosporins/β-lactamase inhibitor and the wider group of sulphonamides/trimethoprim) [15]. Some of these antibiotic FDCs are part of the Watch and Reserve groups of the EML [13], therefore their consumption should be further monitored, investigated and potentially limited to selected indications.

On the other hand, for other combinations there appears to be no potential clinical additional benefit compared to the individual drugs formulated alone, such as those including two drugs belonging to the same class (cefpodoxime proxetile/cefixime, ampicillin/sultamicillin). There is limited evidence supporting the use of the three antibiotic FDCs accounting for the greatest consumption (ampicillin/cloxacillin, cefixime/ofloxacin and metronidazole/spiramycin). The clinical utility of using ampicillin/cloxacillin has been questioned [16–18], as the two antibiotics have overlapping spectra of activity and medical indications that require both these antibiotics as an empiric therapy are not common [16]. Cefixime/ofloxacin was only sold in India where the oral formulation was approved in 2010 for treating typhoid fever [19] in response to the increasing prevalence of Salmonella typhi resistant to quinolones [20]. Two randomized clinical trials are ongoing to compare cefixime/ofloxacin to ofloxacin for the therapy of typhoid fever, and may provide evidence about clinical effectiveness and safety of this combination [21,22]. Metronidazole/spiramycin (indicated for treatment of periodontitis) [23] was sold mainly in France and Vietnam. It has been reported that these two antibiotics have shown synergism in vitro against oral cavity bacteria and their efficacy was similar to amoxicillin-clavulanate but also to metronidazole monotherapy [24]. For this reason, it has been recommended in patients with history of hypersensitivity to amoxicillin/clavulanate.

Concerns regarding clinical efficacy

The approval of antibiotic FDCs may not always require evidence of efficacy and toxicity [7]. Evidence of clinical efficacy and safety of the single components or studies on the combination of the two agents can be sufficient, even if not in a fixed dose ratio [7]. A review of 22 different Indian brands of FDCs containing azithromycin with ofloxacin or cefixime reported that while the formulations contained an adequate dose of fluoroquinolone or cephalosporin, the dose of azithromycin was only 250 mg/tablet (one fifth of the WHO-recommended dose for a 60 kg individual (1200 mg; 10 mg/kg per day)) [25]. In India, dosing of ceftriaxone/vancomycin is recommended twice a day [26]. This dosing frequency is widely accepted for ceftriaxone [27] but administration of vancomycin is usually recommended every 6–8 hours [28].

Concerns regarding safety

There are limited data comparing toxicity resulting from antibiotic FDCs versus monotherapy for conditions other than tuberculosis. However, antibiotic FDCs (particularly those classified as irrational based on the 2012 WHO Essential Drug Model list) have been associated with about 20% of the total adverse drug reactions as a result of antibiotics (26). The combination most commonly associated with adverse events was Ofloxacin/Ornidazole, in terms of cutaneous manifestations [29]. Moreover, some antibiotic FDCs not approved by the FDA include narrow therapeutic index antibiotics such as glycopeptides and aminoglycosides (ceftriaxone/vancomycin, amikacin/cefepime).

Concerns regarding AMR

Gautam et al suggested a possible role of the injudicious use of antibiotic FDCs in the emergence of ciprofloxacin-resistant Salmonella typhi strains in India [30]. However, this is a complex area as the development of antibiotic FDCs may in part be a response to high AMR rates (as with the licensing in India of cefixime/ofloxacin for typhoid fever) [31,32]. Antibiotic FDCs may contribute to AMR by exposing bacteria to sub-therapeutic concentrations of one or both antibiotic components since sub-therapeutic concentrations can exert non-lethal selective pressures [31]. This selection of resistant strains may further contribute to a reduction in clinical effectiveness.

Country specific FDC antibiotic use

Antibiotic FDCs not approved by the US FDA were most commonly sold in middle-income countries, particularly in India, where the sale of US FDA unapproved FDCs accounts for around 50% of antibiotic FDCs and about 16% of overall antibiotics, considerably higher than many other countries. These differences between countries in terms of number and consumption of antibiotic FDCs not approved by the US FDA can be related to several factors, including differences in government regulation [6]. For example, in India, many antibiotic FDCs have historically been sold without authorisation from the Central Drugs Standard Control Organisation (CDSCO), the national regulator [33]. Since 2014/5, the CDSCO has been providing reports of the rationality of FDCs, thus leading the government to ban their manufacture, sale and distribution [4,34]. Among these products, several antibiotics FDCs are listed [35,36].

The many factors which contribute to national differences in consumption of antibiotic FDCs include different prevalence of infectious diseases, access to medical facilities and appropriate diagnostic procedures, accessibility of essential drugs [17], inappropriate prescribing practices [37] and over the counter and non-prescription supply of antimicrobials [1]. Contributing factors for non-prescription antimicrobial supply are poor national medicines regulations, limited availability of qualified pharmacists and commercial pressure on pharmacy staff, consumer demand and lack of awareness of AMR [38]. Two recent studies in China and Vietnam have shown that patients were able to purchase non-prescription antibiotics through various sources (e.g. online pharmacy, illegal drug suppliers) [39,40]. The rationale for individuals using and healthcare workers providing FDC antibiotics should be further explored. Studies are also required to better evaluate their efficacy, effectiveness, safety and potential to accelerate the development of AMR.

Strengths and limitations

To our knowledge, this is the first comprehensive study to assess FDC antibiotic sales at the global level. However, several limitations need to be addressed. The IQVIA database contains aggregate, country-level data without information about indications of therapy, consumers’ age, or setting (hospital, community). The sales data were not adjusted for population size, which partly explains the apparently large contribution of highly populated countries such as India. The IQVIA database is not globally representative (for example, only two low income countries contribute data; these are both part of Francophone West Africa); however, it does provide valuable information on the scale of antibiotic use in the included countries [8]. The IQVIA company estimates coverage for each country internally and applies correction factors to estimate total sales in the sectors covered in each country. Data are also validated against alternative data sources [41]. Despite this uncertainty about the precise volume of FDC antibiotics sold and the validity of comparisons between countries, our analyses support the conclusion that antibiotic FDCs are sold in large volumes in many countries. Finally, it is not possible to distinguish sales of prescription and non-prescription antibiotics in this database.

As discussed above, US FDA authorization cannot be considered as the gold standard measure of a drug’s appropriateness. We use this for illustrative purposes and not to formally assess the appropriateness of particular antibiotic FDCs in a given context; we acknowledge that individual countries may have valid reasons to approve antibiotic FDCs not approved (or not assessed) by the US FDA.

Conclusions

A high consumption of FDC antibiotic globally was observed, particularly in middle-income countries. Antibiotic FDCs account for a substantial proportion of antibiotic consumption and some of these FDCs may not be clinically appropriate, depending on the context. Considering the reported concerns in terms of efficacy, toxicity and AMR, the rationale for using antibiotic FDCs should be explored further and where required studies conducted to assess their effectiveness, safety and potential to accelerate the development of AMR. International initiatives may be needed to regulate the manufacturing and sale of these medications while maintaining access to essential antibiotics, with particular attention to LMICs. Central guidance from the WHO EML could be helpful to assist in determining the clearly inappropriate FDCs and discouraging their manufacture and sale.

Supporting information

S1 Table. Antibiotic FDCs in 2015 sorted by SU globally sold.

(DOCX)

Click here for additional data file. (28.8KB, docx)
S2 Table. Antibiotic FDC categories not approved by US FDA.

(DOCX)

Click here for additional data file. (13.7KB, docx)
S3 Table. Total antibiotic sales and FDCs not approved by the FDA as a percentage of total sales and of total antibiotic FDC sales per each country selling at least one antibiotic FDC not approved by FDA, sorted by the highest not approved FDCs/ antibiotics.

(DOCX)

Click here for additional data file. (17.1KB, docx)
S4 Table. Antibiotic FDCs compatible with WHO EML and AWaRe classes.

(DOCX)

Click here for additional data file. (13.9KB, docx)
S5 Table. Antibiotic FDCs combinations including two highest critically important antibiotics.

(DOCX)

Click here for additional data file. (13.9KB, docx)

Acknowledgments

We are grateful to Peter Stephens for his helpful technical input on the IQVIA-MIDAS data. The findings and suggestions in this paper are based on data obtained under licence from IQVIA information services: IQVIA-MIDAS sale data; all rights reserved. The statement and suggestions are not necessarily those of IQVIA Health Incorporated or any of its affiliated or subsidiary entities.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

We received no specific funding for this work.

References

  • 1.Klein EY, Van Boeckel TP, Martinez EM, et al. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc Natl Acad Sci U S A 2018; 115(15): E3463–E70. 10.1073/pnas.1717295115 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Van Boeckel TP, Gandra S, Ashok A, et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis 2014; 14(8): 742–50. 10.1016/S1473-3099(14)70780-7 [DOI] [PubMed] [Google Scholar]
  • 3.Antibiotics in fixed dose combination. The New England Journal of Medicine 1960; 262(5): 255–6. [Google Scholar]
  • 4.McGettigan P, Roderick P, Kadam A, Pollock A. Threats to global antimicrobial resistance control: Centrally approved and unapproved antibiotic formulations sold in India. Br J Clin Pharmacol 2019; 85(1):59–70. 10.1111/bcp.13503 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Wirtz VJ, Dreser A, Gonzales R. Trends in antibiotic utilization in eight Latin American countries, 1997–2007. Rev Panam Salud Publica 2010; 27(3): 219–25. 10.1590/s1020-49892010000300009 [DOI] [PubMed] [Google Scholar]
  • 6.Poudel A, Mohamed Ibrahim MI, Mishra P, Palaian S. Assessment of the availability and rationality of unregistered fixed dose drug combinations in Nepal: a multicenter cross-sectional study. Glob Health Res Policy 2017; 2: 14 10.1186/s41256-017-0033-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.World Health Organization. Guidelines for registration of fixed-dose combination medicinal products. Technical Report Series, 2005. [Google Scholar]
  • 8.Hsia Y, Sharland M, Jackson C, Wong ICK, Magrini N, Bielicki J. Consumption of oral antibiotic formulations for young children according to the WHO Access, Watch, Reserve (AWaRe) antibiotic groups: an analysis of sales data from 70 middle-income and high-income countries. Lancet Infect Dis 2019. 19(1):67–75. 10.1016/S1473-3099(18)30547-4 [DOI] [PubMed] [Google Scholar]
  • 9.WHO Collaborating Centre for Drug Statistics Methodology. J01 Antibacterial for systemic use. Anatomical Therapeutic Chemical Classification System Available at: https://www.whocc.no/atc_ddd_index/?code=J01&showdescription=yes. Accessed October 20, 2018. [Google Scholar]
  • 10.Goodman LS, Brunton LL, Chabner B, Knollmann BrC. Goodman & Gilman's pharmacological basis of therapeutics 12th ed New York: McGraw-Hill, 2011. [Google Scholar]
  • 11.World Bank. World DataBank: World Development Indicators. Available at: databank.worldbank.org/data/reports.aspx?source=world-development-indicators. Accessed November 10, 2018.
  • 12.Drugs@FDA: FDA Approved Drug Products. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed September 20, 2018.
  • 13.World Health Organization. WHO Model List of Essential Medicines 20th List. 2017. [Google Scholar]
  • 14.World Health Organization. Critically important antimicrobials for human medicine, 5th revision. 2017.
  • 15.Wright H, Bonomo RA, Paterson DL. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin Microbiol Infect 2017; 23(10): 704–12. 10.1016/j.cmi.2017.09.001 [DOI] [PubMed] [Google Scholar]
  • 16.Poudel AP, S. Mohamed Ibrahim MI. Use of ampicillin / cloxacillin combination in Nepal: need for intervention. Gandaki Med J 2008; 1: 61–3. [Google Scholar]
  • 17.Srinivasaraghavan R, Dhandapany G. Non availability of Cloxacillin, A Deterrent for Rational Antimicrobial Practice. Indian Pediatr 2016; 53(11): 1032–3. [PubMed] [Google Scholar]
  • 18.Sharma K, Sharma A, Singh V, Pilania D, Sharma YK. Irrational fixed dose combinations & need for intervention: understanding of dental clinicians and residents. J Clin Diagn Res 2014; 8(12): ZC49–52. 10.7860/JCDR/2014/10273.5294 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Bakthavatchalam YD, Kumar DT, Tayubi IA, et al. In vitro efficacy and in silico analysis of cefixime-ofloxacin combination for Salmonella Typhi from bloodstream infection. J Appl Microbiol 2017; 123(3): 615–24. 10.1111/jam.13522 [DOI] [PubMed] [Google Scholar]
  • 20.Faruqui DAA, Siddique W. Evaluation of efficacy and safety of fixed dose combination of Cefixime and Ofloxacin (CO2 Tablet) in the management of typhoid fever. Indian Journal of Basic & Applied Medical Research 2012; 1(4): 296–303. [Google Scholar]
  • 21.A clinical trial to study the effects of drus, Cefixime and Ofloxacin versus ofloxacin in Patients with Typhoid Fever Available at: http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=1367 Accessed November 15, 2018.
  • 22.A clinical trial to study the effects of two drugs,Cefixime SR and Ofloxacin SR in Patients with Typhoid Fever Available at: http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=1697 Accessed November 15, 2018.
  • 23.Haffajee AD, Socransky SS, Gunsolley JC. Systemic anti-infective periodontal therapy. A systematic review. Ann Periodontol 2003; 8(1): 115–81. 10.1902/annals.2003.8.1.115 [DOI] [PubMed] [Google Scholar]
  • 24.Poulet PP, Duffaut D, Barthet P, Brumpt I. Concentrations and in vivo antibacterial activity of spiramycin and metronidazole in patients with periodontitis treated with high-dose metronidazole and the spiramycin/metronidazole combination. J Antimicrob Chemother 2005; 55(3): 347–51. 10.1093/jac/dki013 [DOI] [PubMed] [Google Scholar]
  • 25.Veeraraghavan B, Pragasam AK, Bakthavatchalam YD, Ralph R. Typhoid fever: issues in laboratory detection, treatment options & concerns in management in developing countries. Future Sci OA 2018; 4(6): FSO312 10.4155/fsoa-2018-0003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Ceftriaxone-Vancomicin. Available at: http://www.drugsupdate.com/. Accessed November 5, 2018.
  • 27.Ceftriaxone. Available at: https://bnfc.nice.org.uk/drug/ceftriaxone.html. Accessed November 5, 2018.
  • 28.Vancomycin. Available at: https://bnfc.nice.org.uk/drug/vancomycin.html Accessed November 5, 2018.
  • 29.Richa Tandon VR, Sharma S, Khajuria V, Mahajan V, Gillani Z. Adverse drug reactions profile of antimicrobials: A 3-year experience, from a tertiary care teaching hospital of India. Indian J Med Microbiol 2015; 33(3): 393–400. 10.4103/0255-0857.158564 [DOI] [PubMed] [Google Scholar]
  • 30.Gautam CS, Saha L. Fixed dose drug combinations (FDCs): rational or irrational: a view point. Br J Clin Pharmacol 2008; 65(5): 795–6. 10.1111/j.1365-2125.2007.03089.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Holmes AH, Moore LS, Sundsfjord A, et al. Understanding the mechanisms and drivers of antimicrobial resistance. Lancet 2016; 387(10014): 176–87. 10.1016/S0140-6736(15)00473-0 [DOI] [PubMed] [Google Scholar]
  • 32.Mehta KC, Dargad RR, Borade DM, Swami OC. Burden of antibiotic resistance in common infectious diseases: role of antibiotic combination therapy. J Clin Diagn Res 2014; 8(6): ME05–8. 10.7860/JCDR/2014/8778.4489 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Dalal K, Ganguly B, Gor A. Assessment of Rationality of Fixed Dose Combinations Approved in CDSCO List. J Clin Diagn Res 2016; 10(4): FC05–8. 10.7860/JCDR/2016/17856.7691 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Central drugs standard control organization. Report of expert committee on evaluation of cases of fixed dose combinations except vitamins and mineral preparations 2016.
  • 35.Government bans Saridon, 327 other combination drugs. Available at: https://timesofindia.indiatimes.com/india/govt-bans-popular-painkiller-327-other-unsafe-fixed-dose-drugs/articleshow/65790311.cms. Accessed September, 2018.
  • 36.Indian Health Ministry Bnned 329 controversial fixed dose combination with immediate effect. Available at: https://nckpharma.com/indian-health-mistry-banned-329-controversial-fixed-dose-combination-with-immediate-effect/. Accessed September 2020.
  • 37.Goswami N, Gandhi A, Patel P, Dikshit R. An evaluation of knowledge, attitude and practices about prescribing fixed dose combinations among resident doctors. Perspect Clin Res 2013; 4(2): 130–5. 10.4103/2229-3485.111797 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Sakeena MHF, Bennett AA, McLachlan AJ. Non-prescription sales of antimicrobial agents at community pharmacies in developing countries: a systematic review. Int J Antimicrob Agents 2018;52(6):771–782. 10.1016/j.ijantimicag.2018.09.022 [DOI] [PubMed] [Google Scholar]
  • 39.Nguyen HH, Ho DP, Vu TLH, Tran KT, Tran TD, Nguyen TKC, et al. "I can make more from selling medicine when breaking the rules"—understanding the antibiotic supply network in a rural community in Viet Nam. BMC Public Health. 2019. Nov 26;19(1):1560 10.1186/s12889-019-7812-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Gong Y, Jiang N, Chen Z, Wang J, Zhang J, Feng J, et al. Over-the-counter antibiotic sales in community and online pharmacies, China. Bull World Health Organ. 2020. Jul 1;98(7):449–457. 10.2471/BLT.19.242370 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.IQVIA, 2018. ACTS: IQVIA Quality assurance. Available: https://www.iqvia.com/landing/acts [Accessed 10 Oct 2020].

Decision Letter 0

Iddya Karunasagar

6 Mar 2020

PONE-D-20-01816

High global consumption of potentially inappropriate fixed dose combination antibiotics: analysis of data from 75 countries

PLOS ONE

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

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Additional Editor Comments (if provided):

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. 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

Reviewer #2: 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 #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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

Reviewer #1: I read the manuscript with interest. I appreciate the authors for focusing the study on the issue of use of fixed dose combinations. The manuscript presents consumption data of fixed dose combinations from 75 countries with limited data available.

Reviewer #2: The manuscript by Hsia Y and colleagues report on the high consumption of fixed dose combination (FDC) antibiotics globally from 75 countries by utilizing a pharmaceutical database, IQVIA-Multinational Integrated Data Analysis System (IQVIA- MIDAS). They conclude that India, China and Vietnam had the highest sales of FDC antibiotics, majority of which did not have approval by the United States Food and Drug Administration (U.S. FDA) and the World Health Organization (WHO) Essential Medicines List (EML).

Introduction:

a. Expand on the introduction to include details about 2017 WHO Essential Medicine List and National List of Essential Meds (NLEMs).

b. Mention and define WHO classification of antibiotics with citation of appropriate reference [ref 13].

Methods:

a. ?Ecological study

b. Describe antibiotic sales data in more detail as captured in the IQVIA database. For example, mention the sources of the sales audit were collected (besides pharmaceutical industries, ?distributers, ?sub-stockists, ?retailers and hospitals, and ?dispensing physicians, etc.

c. What is the percentage of national antibiotic sales for India, China and Vietnam captured in the IQVIA database?

d. Are the sales volume reported monthly? Please clarify.

e. How many investigators examined the IQVIA database? Was any discrepancy observed?

f. Mention exclusion criteria if any?anti-TB drugs, antivirals, antifungals, etc

g. Please indicate if your study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology – Antimicrobial Studies (STROBE-AMS) for reporting..if Yes, please state and cite reference Tacconelli E, et al. BMJ Open 2016;6:e010134.

Results:

a. Mention sales of unapproved single-drug formulations (SDFs) if data captured in the IQVIA database.

Discussion:

a. The authors must discuss their Recommendations in more detail in a separate paragraph

- Government ban, Regulation for MNCs to justify sale of unapproved products. Public awareness of approved FDC. (Holloway KA, et al. PLoS ONE 2016;11:e0152020)

Mention if there is data on why clinicians choose unapproved antibiotic FDCs in countries such as India and China? Role of MNCs, conflict of interest, etc.

b. Study Limitations:

- ?possibility of error in sampling methodology.

- Can the IQVIA database distinguish sales of prescription vs. non-prescription antibiotics. This should be mentioned in the limitations.

References:

a. Reference 4 – cite year, volume, page no for Br J Clin Pharmacol.

b. Reference 36 – newspaper article, cite online link if available

c. Reference 38 – cite volume, page no

d. Please follow journal instructions for formatting of references

**********

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Reviewer #2: No

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PLoS One. 2021 Jan 20;16(1):e0241899. doi: 10.1371/journal.pone.0241899.r002

Author response to Decision Letter 0

1 Oct 2020

Reviewer #1: I read the manuscript with interest. I appreciate the authors for focusing the study on the issue of use of fixed dose combinations. The manuscript presents consumption data of fixed dose combinations from 75 countries with limited data available.

Response: Thank you.

Reviewer #2: The manuscript by Hsia Y and colleagues report on the high consumption of fixed dose combination (FDC) antibiotics globally from 75 countries by utilizing a pharmaceutical database, IQVIA-Multinational Integrated Data Analysis System (IQVIA- MIDAS). They conclude that India, China and Vietnam had the highest sales of FDC antibiotics, majority of which did not have approval by the United States Food and Drug Administration (U.S. FDA) and the World Health Organization (WHO) Essential Medicines List (EML).

Introduction:

a. Expand on the introduction to include details about 2017 WHO Essential Medicine List and National List of Essential Meds (NLEMs).

Response: Thank you for the comment. We have expanded and included details about 2017 WHO Essential Medicine List (EML) in the Introduction to place the rationale for our study in a global context.

‘In 2017, the WHO Essential Medicines List (EML) Working Group classified antibiotics in the EML and EML for Children (EMLc) into three groups: Access, Watch, and Reserve (AWaRe classification). The Access group contains generally narrow spectrum antibiotics recommended as first and second choice for most common clinical infection syndromes. The Watch group contains broader spectrum antibiotic classes corresponding to the highest priority agents on the list of critically important antimicrobial drugs for human medicine. The Reserve group consists of last resort antibiotics for targeted use in multidrug resistant infections (Sharland et al., 2018). The new AWaRe classification is intended to be easy to apply to monitor antibiotic use and inform antibiotic stewardship.’

The primary purpose of the National List of Essential Medicines of India (NLEM) aims to promote rational use of medicines in India. Our study aimed to characterise global FDC antibiotics sales, we have not described guidance for individual countries (such as the NLEM of India) in our manuscript. [1]

Methods:

a. ?Ecological study

Response: This is an ecological study and we have added this to the revised manuscript.

b. Describe antibiotic sales data in more detail as captured in the IQVIA database. For example, mention the sources of the sales audit were collected (besides pharmaceutical industries, ?distributers, ?sub-stockists, ?retailers and hospitals, and ?dispensing physicians, etc.

Response: Thank you for raising these comments. IQVIA-MIDAS is a commercial database. The data contained in the database were obtained from pharmacy retail sales throughout the supply chain, including overall antibiotic volume sold to retails and hospital pharmacies by wholesalers. IQVIA data were not contributed from all wholesalers in represented countries, adjustments had been made by the providers of the database to estimate total sales based on the market share of participating wholesalers. We don’t now know how IQVIA company estimate country-level coverage as those information are not publicly available.

We have added more detailed on data captured in the IQVIA-MIDAS database in the revised manuscript.

c. What is the percentage of national antibiotic sales for India, China and Vietnam captured in the IQVIA database?

Response: Unfortunately this information is not publicly available; however, the database as supplied includes adjustments for country-specific coverage as estimated by IQVIA to “scale up” to the total sales in the sector(s) covered in that country. The IQVIA database are internally validated against alternative source of sale data. We acknowledge this limitation and now include it in the Discussion section.

d. Are the sales volume reported monthly? Please clarify.

Response: The database contains only annual sales volume and we have clarified this in the Methods section.

e. How many investigators examined the IQVIA database? Was any discrepancy observed?

Response: We have three investigators (BB, CJ, YH) checked and compare classification of products as FDC antibiotics. There was no discrepancy was observed in our dataset.

f. Mention exclusion criteria if any?anti-TB drugs, antivirals, antifungals, etc

Response: We did not include anti-TB drugs, antiviral drugs, and antifungals in our database. We have added the exclusion criteria in our revised manuscript.

g. Please indicate if your study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology – Antimicrobial Studies (STROBE-AMS) for reporting..if Yes, please state and cite reference Tacconelli E, et al. BMJ Open 2016;6:e010134.

Response: Thank you for the comment. We agree with reviewer that we should adhere to the STROBE-AMS. This statement is aimed at ‘epidemiologic studies focused on the link between antimicrobial resistant bacteria and antibiotic usage’. Our study only investigate the antibiotic usage so many items on the checklist are not relevant to our study. We did not adhere to all items on the checklist but we included a general on STROBE checklist when we conducted this study.

Results:

a. Mention sales of unapproved single-drug formulations (SDFs) if data captured in the IQVIA database.

Response: We agree with the reviewer that it is also important to assess sales of unapproved single-drug formulations. However, this is the beyond the scope of this study. We appreciate the reviewer’s valuable comment and will consider further exploring the sales of unapproved single-drug formulations in future work.

Discussion:

a. The authors must discuss their Recommendations in more detail in a separate paragraph

- Government ban, Regulation for MNCs to justify sale of unapproved products. Public awareness of approved FDC. (Holloway KA, et al. PLoS ONE 2016;11:e0152020)

Response: Thank you for the comments and we appreciate the useful reference. We agree with reviewer’s point of view.

FDC antibiotic is a complex issue. Determining the evidence for the use of FDC antibiotics is the first step for policy makers to strengthen regulations for manufacturing these drugs. However, there is currently a lack of summarised international evidence to support the use of FDC antibiotics. We contacted a literature review for ampicillin-cloxacillin with the primary objective of summarising available data on the safety and efficacy of this FDC antibiotic. Our review highlights difficulties in accessing some potentially informative literature, particularly studies published in non-English language journals (paper is currently under review). We believe the best practical recommendation is the central guidance from the organization such as WHO could be helpful to assist to determine the clearly inappropriate FDC use. We already discuss this recommendation in Discussion section.

-Mention if there is data on why clinicians choose unapproved antibiotic FDCs in countries such as India and China? Role of MNCs, conflict of interest, etc.

Response: We are not clear if reviewer refers to ‘quantitative data’ for this comment. If so, we are not aware any quantitative data to explore why clinicians choose unapproved antibiotic FDCs in India and China. However, there is a recent qualitive study conducted in Vietnam to interview 16 suppliers on their knowledge of antibiotics and antibiotic resistance: 1 hospital pharmacy; 1 commune health centre; 8 private dispensaries; 1 traditional medicine centre; 2 private clinics; 3 other types of selling antibiotics. This study highlights that patients were able to purchase antibiotics through different suppliers. The habit of using antibiotics driven not only by clinicians’ prescribing behaviour also suppliers and patients (‘customers’). [2] As we discussed above, the more practical recommendation should be the central guidance from WHO EML department.

b. Study Limitations:

- ?possibility of error in sampling methodology.

Response: We acknowledge that the data provided to IQVIA-MIDAS may not be fully representative of antibiotic consumption in each contributing country. The IQVIA company does estimate coverage for each country internally and applies correction factors to estimate total sales in the sectors covered in each country. Data are also validated against alternative data sources. [3]

The database do not represent precise estimates of antibiotic FDC sales (they are likely to underestimate sales due to incomplete coverage) and that there are difficulties in comparing between countries. Despite this, our analysis indicates that FDCs are widely used throughout HICs and LMICs and we consider our conclusion that much of this use may be inappropriate and regulation should be explored is valid, even if we have not fully quantified sales. We acknowledge this and several other caveats which we all addressed in the Discussion.

‘The sales data were not adjusted for population size, which partly explains the apparently large contribution of highly populated countries such as India. The IQVIA database is not globally representative (for example, only two low income countries contribute data; these are both part of Francophone West Africa); however, it does provide valuable information on the scale of antibiotic use in the included countries. The IQVIA company estimates coverage for each country internally and applies correction factors to estimate total sales in the sectors covered in each country. Data are also validated against alternative data sources’.

- Can the IQVIA database distinguish sales of prescription vs. non-prescription antibiotics. This should be mentioned in the limitations.

Response: We agree that this would be an important distinction, but unfortunately it is not possible to use the IQVIA-MIDAS database to distinguish sales of prescription vs non-prescription antibiotics. We acknowledge this limitation and have addressed it in the Discussion section : ‘Finally, it is not possible to distinguish sales of prescription and non-prescription antibiotics in this database’

References:

a. Reference 4 – cite year, volume, page no for Br J Clin Pharmacol.

b. Reference 36 – newspaper article, cite online link if available

c. Reference 38 – cite volume, page no

d. Please follow journal instructions for formatting of references

Response: Thank you for noting these errors, we have now corrected these references and follow the journal instructions for formatting the references.

References

1. National List of Essential Medicines of India 2011. Avalable : https://pharmaceuticals.gov.in/sites/default/files/NLEM.pdf. [Accessed 10 Oct 2020]

2. Nguyen HH, Ho DP, Vu TLH, Tran KT, Tran TD, Nguyen TKC, van Doorn HR, Nadjm B, Kinsman J, Wertheim H. "I can make more from selling medicine when breaking the rules" - understanding the antibiotic supply network in a rural community in Viet Nam. BMC Public Health. 2019 Nov 26;19(1):1560.

3. IQVIA, 2018. ACTS: IQVIA Quality assurance. Available: https://www. iqvia.com/landing/acts [Accessed 10 Oct 2020].

Attachment

Submitted filename: Reviewers responses final.docx

Click here for additional data file. (23KB, docx)

Decision Letter 1

Iddya Karunasagar

23 Oct 2020

High global consumption of potentially inappropriate fixed dose combination antibiotics: analysis of data from 75 countries

PONE-D-20-01816R1

Dear Dr. Hsia,

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.

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Kind regards,

Iddya Karunasagar

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

All reviewer comments have been addressed.

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 #2: 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 #2: Yes

**********

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

Reviewer #2: Yes

**********

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 #2: 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 #2: 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 #2: Thank you for revising the manuscript. The authors have addressing all the comments from the reviewer.

**********

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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 #2: No

Acceptance letter

Iddya Karunasagar

2 Dec 2020

PONE-D-20-01816R1

High global consumption of potentially inappropriate fixed dose combination antibiotics: analysis of data from 75 countries

Dear Dr. Hsia:

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.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

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on behalf of

Dr. Iddya Karunasagar

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Antibiotic FDCs in 2015 sorted by SU globally sold.

    (DOCX)

    Click here for additional data file. (28.8KB, docx)
    S2 Table. Antibiotic FDC categories not approved by US FDA.

    (DOCX)

    Click here for additional data file. (13.7KB, docx)
    S3 Table. Total antibiotic sales and FDCs not approved by the FDA as a percentage of total sales and of total antibiotic FDC sales per each country selling at least one antibiotic FDC not approved by FDA, sorted by the highest not approved FDCs/ antibiotics.

    (DOCX)

    Click here for additional data file. (17.1KB, docx)
    S4 Table. Antibiotic FDCs compatible with WHO EML and AWaRe classes.

    (DOCX)

    Click here for additional data file. (13.9KB, docx)
    S5 Table. Antibiotic FDCs combinations including two highest critically important antibiotics.

    (DOCX)

    Click here for additional data file. (13.9KB, docx)
    Attachment

    Submitted filename: Reviewers responses final.docx

    Click here for additional data file. (23KB, docx)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.

    Articles from PLoS ONE are provided here courtesy of PLOS

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