Antibiotic Use and Misuse in Dentistry in India—A Systematic Review

Background: Infections caused by antibiotic resistance pose a serious global health threat, undermining our ability to treat common infections and deliver complex medical procedures. Antibiotic misuse, particularly in low-–middle-income countries, is accelerating this problem. Aim: The aim of this systematic review was to investigate the use and misuse of antibiotics in dentistry in India. Method: We included studies carried out on Indian populations evaluating the prescription of prophylactic or therapeutic antibiotics by dental practitioners or other healthcare providers, along with antibiotic self-medication by the general population. The primary outcome measure was prescription rate/use of antibiotics for dental/oral problems. The secondary outcome measures included indications for antibiotic use in dentistry, their types and regimens, factors influencing practitioners’ prescription patterns and any differences based on prescriber and patient characteristics. Multiple databases were searched with no restrictions on language or publication date. The quality assessment of all included studies was carried out using the AXIS tool for cross-sectional studies and the Joanna Briggs Institute checklist for qualitative studies. Results: Of the 1377 studies identified, 50 were eligible for review, comprising 35 questionnaire surveys, 14 prescription audits and one qualitative study (semi-structured interviews). The overall quality of the included studies was found to be low to moderate. The proportion of antibiotic prescriptions amongst all prescriptions made was found to range from 27% to 88%, with most studies reporting antibiotics in over half of all prescriptions; studies also reported a high proportion of prescriptions with a fixed dose drug combination. Worryingly, combination doses not recommended by the WHO AWaRe classification were being used. The rate of antibiotic self-medication reported for dental problems varied from 5% to 35%. Conclusions: Our review identified the significant misuse of antibiotics for dental diseases, with inappropriate use therapeutically and prophylactically, the use of broad spectrum and combination antibiotics not recommended by WHO, and self-medication by the general population. There is an urgent need for targeted stewardship programmes in this arena.


Introduction
Infections caused by antimicrobial-resistant organisms kill at least 700,000 people every year, and could cause 10 million deaths by the year 2050, a loss of 100 trillion US dollars to the global economy, and a 2-3.5% reduction in the world's GDP, if left unchecked [1]. They therefore constitute a serious global health threat that makes treating common infections as well as delivering complex medical procedures a challenge [2,3]. Although resistance is a normal evolutionary process for microorganisms, it is accelerated by the widespread use of 2.
Clinical (therapeutic/prophylactic) and non-clinical indications where antibiotics are prescribed in dentistry; 3.
The types and regimen of antibiotics used; 4.
The difference, if any, between rural and urban populations, adults and children, males and females, and socioeconomic classes; 5.
Differences in antibiotic prescription based on provider characteristics; 6.
The factors influencing practitioners' prescription patterns; and 7.
The reasons for self-medication with antibiotics and their sources.

Information Sources and Search Strategy
The following electronic databases were searched from their inception until 29th Feb 2020: Cochrane Database of Systematic Reviews, EMBASE, MEDLINE (Ovid), CINAHL, International Pharmaceutical Abstracts, Global Health, Web of Science and Google Scholar. The search was updated on 7 November 2021 to include any new studies. Supplementary  Table S1 shows the search strategy for the above databases. Key search terms included antibiotic, antimicrobial, antibacterial, drug resistance, overuse, misuse, consumption, inappropriate prescription, self-medication, knowledge, stewardship, survey, dentistry, dentists, pharmacists, physicians, and health services.
Dissertation data (www.theses.com, accessed on 7 November 2021) and grey literature (www.opengrey.eu, accessed on 7 November 2021) were searched for on-going and unpublished studies. The reference lists of all eligible studies were checked for additional studies. Hand-searching of selected journals (Indian Journal of Dental Research, Journal of Indian Association of Public Health Dentistry) was performed in order to identify any missed studies. No language restriction was applied, and there was no restriction on the date of publication.

Inclusion Criteria
Studies carried out in India and on Indian populations and those that were available electronically were included. Studies that evaluated the prescription of prophylactic or therapeutic antibiotics by general dental practitioners, specialist dental practitioners (dentists with additional training and included in the Dental Council of India's specialist register) or other healthcare providers for dental problems were considered eligible. Studies reporting on self-medication by the general population for dental problems were also included.

Exclusion Criteria
Exclusion criteria included: • Case reports and case series; • Studies involving dental students; • Studies performed in vitro; and Studies examining the use of antibacterial mouthwashes and other oral rinses, oral mucosal/gingival gels (antibiotic gels were included).

Research Question
Among adults and children with dental/oral health problems in India, what are the rates and indications for the use of antibiotics?
The following criteria (PICO-Population, Intervention/Exposure, Comparison, Outcome) were applied when considering studies for this review.
Population: Adults and children living in both urban and rural India, who: • were seeking treatment from dental practitioners, dental specialists or other healthcare providers (including general medical practitioners, informal healthcare providers, etc.) for oral/dental problems; or • had taken at least one course of antibiotics to help with dental/oral problems (irrespective of whether they completed the course or not), without consulting a dentist or other health practitioner (self-medication).
Intervention/Exposure: The review focused on exposure to antibiotics/consumption within the Indian population, both prescribed and self-medication.
Comparison: The study did not have a comparison arm. Outcome measures: The primary outcome measures were the prescription rate of antibiotics for dental/oral problems in India and their indications. This also included the rate of over-the-counter antibiotic use (self-medication) for dental problems.
Secondary outcomes: Where data were available, we evaluated: 1.
Indications for dental antibiotic prescription: clinical (therapeutic/prophylactic) and non-clinical.

2.
The types and regimens of antibiotics used. 3.
The difference, if any, between rural and urban populations, adults and children, male and female, and socioeconomic classes. 4.
The factors influencing practitioners' prescription patterns, e.g., source of knowledge, such as monographs, textbooks and journals, colleagues, continuing professional development programmes, etc. 6.
The sources of antibiotics, if self-prescribed, and the reasons for self-medication.

Study Screening and Selection
The screening and selection process was carried out in accordance with the Preferred Reporting Items in Systematic Reviews and Meta-Analyses [40]. After literature retrieval, studies were exported to EndNote (Clarivate Analytics) and deduplicated before review. Two authors (AB, HL) independently reviewed the titles and abstracts and excluded all irrelevant studies. Full texts were obtained for potentially eligible articles and those where a clear decision could not be made from the title and abstract alone. These articles were carefully examined for compliance with our inclusion and exclusion criteria. Any discrepancies in study inclusion were resolved after discussion with a third reviewer (VA).

Data Extraction and Synthesis
Data extraction for all included studies was performed independently and in duplicate by both the authors (AB, HL), and any discrepancies were resolved through discussion and consultation with a third reviewer (VA). The customised data extraction form was piloted and both authors (AB, HL) extracting the data participated in the piloting so that they were clear about the extraction process. The data extraction form included details on authors, year of publication, study setting, demographic details of prescriber and patients, rate of antibiotic use, details of antibiotics used and indications and details of self-medication. A sample data extraction form is attached in Supplementary Table S2. Changes and refinements to the form were carried out through discussion with all authors as part of the piloting process. Three groups of studies were identified in the literature that reported three key areas of antibiotic use for dental problems in India:

1.
Studies exploring antibiotic prescription rates by dentists and other healthcare providers for dental problems; 2.
Studies that investigated self-medication practices by the general population for dental/oral problems; and 3. Studies that explored indications, and the knowledge and practice of dentists in prescribing antibiotics for dental conditions.

Data Analysis
Data were descriptively analysed with mean percentages (standard deviations) for all quantitative outcomes. Forest plots were used where possible to display the effect sizes, and heterogeneity was determined using I2 analysis. The "meta" package in R version 4.0.0 was used to generate forest plots. Thematic analysis was performed for qualitative outcomes.

Rate of Antibiotic Use
To address this objective, we extracted data from prescription audits and hospital case record analysis of prescriptions and reported prescriptions containing antibiotics as a percentage of the total prescriptions made for dental/oral problems. The use of multiple antibiotics and/or fixed dose combinations was also identified and reported.
Where studies were carried out for other medical conditions, and included prescriptions for dental problems, we reported the proportion of these dental prescriptions compared to those issued for other medical conditions as a percentage.
To report the proportion of antibiotic self-medication, we extracted data from questionnaire studies involving the self-reported use of antibiotics for dental problems. These data were reported as percentages of the overall self-medicating population. Where the reasons for antibiotic self-medication were assessed for all health problems, the proportion of people self-medicating for dental problems was extracted.

Clinical and Non-Clinical Indications for Prescribing Antibiotics
We extracted data from questionnaire studies involving the antibiotic prescription patterns of dental practitioners for various dental/oral conditions. These data were tabulated as therapeutic clinical indications, where antibiotics were prescribed to treat dental disease (either alone or in combination with an operative intervention) and prophylactic clinical indications, to prevent infection either at the surgical site (e.g., minor dental surgeries) or at a distant site (e.g., prophylaxis for infective endocarditis).
Free-text responses related to clinical and non-clinical indications for prescribing (e.g., time constraints/patient pressures) were collated and reported quantitatively where possible. Where data were available, t-tests were used to examine significant differences between the antibiotic prescription pattern between groups (e.g., between dentists with and without postgraduate qualifications).

Types and Regimen of Antibiotics Used
We extracted data about the types of antibiotics used from knowledge-based questionnaire studies and prescriptions involving dental practitioners and informal healthcare providers and classified these according to the World Health Organisation AWaRe (Access, Watch, Reserve) Classification [41], and whether they were included in India's National List of Essential Medicines 2015 [42]. The WHO AWaRe Database was developed in 2019 to enable the optimal use of antibiotics by countries and reduce antibiotic resistance. The Access group includes antibiotics with lower resistance potential and that are active against common pathogens. The Watch group antibiotics have a higher resistance potential and are key targets of stewardship programmes. The Reserve group are "last resort" antibiotics reserved for multi-drug-resistant organisms. In addition, the database also lists a number of fixed dose combinations of multiple broad-spectrum antibiotics whose use in not evidence-based and is therefore not recommended.
Where available, the antibiotic regimen (combinations used, frequency/dose) was extracted. Any differences in the pattern of antibiotic use (prescription/self-prescription) among various population groups (for example, rural/urban; adult/child; male/female; different socioeconomic strata) or among providers (dentists vs. specialist dentists vs. non-dental prescribers; male/female; rural/urban), where reported, were extracted.
To address the other objectives, data regarding factors influencing practitioners' prescription pattern and their source of prescription knowledge were recorded.
From the studies involving self-medicating populations, the reasons for antibiotic self-medication for dental problems and the sources of antibiotics were extracted and tabulated.

Quality Assessment
The quality assessment of all included studies was carried out using the AXIS (Appraisal of Cross-sectional studies) tool [43]. The studies involving qualitative research were assessed using JBI (Joanna Briggs Institute) checklist [44].
The AXIS tool does not provide an overall numerical score to classify studies based on quality. However, in this review, we categorised the overall quality of included studies based on the following criteria for ease of understanding: a score of 17 or above was classified as high quality (low risk of bias), a score between 13 and 16 was classified as moderate quality (moderate risk of bias), and a score below 13 was considered low quality (high risk of bias).

Results
The search strategy identified 1226 studies, and after the removal of duplicates and title and abstract screening process, 96 studies were retrieved. A thorough citation search and website search resulted in the identification of a further 151 articles, of which 35 were included. Full-text analysis was performed for these 131 studies and 50 were considered as being eligible for inclusion in our review. Figure 1 shows the PRISMA flow chart for study screening and selection.

Study Characteristics
The characteristics of all included studies can be found in Table 1.

Study Design
Of the fifty studies, 49 studies involved quantitative research and reported the number and percentages of antibiotic prescriptions and indications for use. One study involved qualitative research and assessed the perception of prescribers about drivers of antibiotic resistance in dentistry, through open-ended interviews.
Among the quantitative research, most were questionnaire surveys (n = 32) or prescription audits (n = 12). Two studies analysed hospital case records of patients, two were questionnaire-based interviews and one study involved simulated patients.
Twenty-six studies [32][33][34][35] explored the indications and reasons for antibiotic prescription/dispensing. Of these, 25 studies involved questionnaire surveys of dentists, and one study [38] involved antibiotic dispensing by pharmacists without a prescription to patients with dental complaints. Additionally, one study [88] was qualitative in nature, involving both dentists and pharmacists. This qualitative study adapted the grounded theory approach to understand the perceptions, beliefs and experiences of dentists and pharmacists.

Quality Assessment
The quality assessment of our included studies is summarised in Supplementary Table S3a,b.
All the studies except for the study involving a qualitative design [88] were assessed using the AXIS tool.
Selection process, non-responders, response rate information and information on non-responders were the domains that frequently introduced bias. Additionally, the measurement tool used/piloted and the repeatability of the methods were the two domains frequently assessed as providing high levels of risk of bias in the included studies. However, in providing our specified outcome data, most studies reported this accurately and were deemed as having low/moderate risk regarding outcome reporting.

Primary Outcomes
Rate of Antibiotic Use for Dental/Oral Problems a.
Rate of antibiotic prescriptions in clinical dental settings The overall proportion of antibiotic prescriptions was reported by five prescription audits [38,45,[49][50][51] involving 3556 prescriptions. Heterogeneity calculation that was carried out using I 2 analysis showed a very high percentage (I 2 = 99.53%). Figure 2 (Forest plot) shows that in four of these studies, over half of the prescriptions for oral/dental problems contained one or more antibiotics. In addition, three studies reported on the proportion of fixed drug dose combinations (FDCs) in all antibiotic prescriptions; of these, one study [50] involving a child population reported FDCs in 20% of antibiotic prescriptions, while the remaining two studies [48,52] involving rural adult populations reported 28% each. An FDC is a combination of two or more active pharmacological ingredients in a fixed ratio of doses [91].

b.
Rate of over-the-counter antibiotic use (self-medication) for dental problems Seven studies [58][59][60][61][63][64][65] explored the prevalence of self-medication practices for oral/dental problems in 1580 patients. Five of these studies [58,59,[63][64][65] reported the proportion of patients self-medicating with antibiotics out of the total number of selfmedicating patients in the study. Of these, one study involved a rural population [63] and reported antibiotic self-medication at a rate of 10%, while the remaining four involving urban settings (Figure 3) showed the spread of antibiotic self-medication to be between 5% and 35%. Similar to the antibiotic prescription rate, the heterogeneity calculations for the self-medication rate were also high (I 2 = 98.80%). Additionally, 38.04% of self-medicating patients did not know what drug they were taking [60]. Only one study explored antibiotic self-medication in the community and found that 42.3% of the study population selfmedicated with antibiotics for dental problems/pain, a proportion surpassed only by fever (76.8%) and cough and flu (70.8%) [66]. c.
Rate of antibiotics prescribed in dentistry compared to other healthcare fields Two studies [38,47] evaluated the percentage of antibiotic prescriptions for dental diseases compared to other medical conditions ( Table 2). The study by Khare et al. [38] evaluated 11,336 antibiotic prescriptions of informal healthcare providers in a rural setting. The results show that 9.9% (1273 prescriptions) of all antibiotic prescriptions were for oral/dental problems (compared with 31.5% for fever (unspecified cause), 28.9% for upper respiratory tract infections, 11.2% for gastro-intestinal disorders and 7.5% for skin infections).
One study [47] that included both rural and urban populations identified 353 dental antibiotic encounters of a total of 10,800 antibiotic encounters in small hospitals, GP clinics and pharmacy shops. The dental reasons accounted for 3.3% of the overall antibiotic prescriptions/dispensations (compared to 21.2% for fever, 19.7% for upper respiratory tract infections, 11.5% for lower respiratory tract infections, 6.5% for gastrointestinal problems, 5.3% for skin and soft tissue problems, 4.8% for UTIs and 9% for wounds, 4% for cardiovascular reasons and 3.2% for surgery-related issues, among others) [47].

Indications for Antibiotics
The various indications of antibiotic use identified from our studies are summarised in Tables 3-6.
Patient symptoms were considered an important factor favouring the prescription of antibiotics [80,88].
Antibiotics were also prescribed to prevent infection in distant sites, such as in cardiac conditions.

Antibiotics Used Types and Regimen of Antibiotics
Only a few studies provided the regimen of antibiotics used, and there was great variation in the type and regimen of antibiotics prescribed across studies (Supplementary  Table S4).
Amoxicillin was found to be the most commonly used antibiotic for therapeutic and prophylactic indications, prescribed either alone or in combination with clavulanic acid.
Doxycycline and metronidazole were preferred in periodontal management [34,69,75], although both these drugs were used for other dental indications as well. Metronidazole or a nitroimidazole antibiotic was often combined with other antibiotics such as amoxycillin or amoxicillin + clavulanic acid for anaerobic coverage [67,72,73].
In total, 32 prescribing patterns were identified where antibiotics were prescribed either singly (n = 23) or in combination with other antibiotics or as a fixed dose combination of more than one drug/antibiotic (n = 9). Among the 23 individual antibiotics identified in our review, twelve are included under the WHO "Access" category and eleven under the "Watch" category ( Figure 4) [41]. Thirteen of these 23 individual antibiotics are included in India's National List of Essential Medicines (NLEM) 2015 [42]. Of the nine combinations/FDCs used, only two (amoxicillin/clavulanic acid and co-trimoxazole) are included in the 'Access' category as well as the NLEM of India. The WHO's AWaRe [41] category does not recommend the use of the remaining seven antibiotic combinations in clinical practice (Figure 4). Only four studies [38,51,52,79] reported the route of antibiotic administration. Oral administration was the most preferred choice for dentists, with a range of 86.5% to 100% prescribing antibiotics orally.
Combination Antibiotics and Fixed Dose Drug Combinations (FDC) a.
While the use of ofloxacillin + ornidazole and ciprofloxacillin + tinidazole combinations has been identified in patients with and without a penicillin allergy, the former combination was also reported in child patients [73].

b. Combinations Identified from Prescription Audits (Actual Prescriptions)
The use of combination antibiotics was identified in five prescription audits. The proportion of such antibiotics varied between studies. The mean prescription rate for amoxicillin + clavulanic acid was found to be 15.9% (SD 16.04) [38,48,52,54], and that for ofloxacillin + ornidazole combination was 13.4% (SD 14.7) [45,52]. The study by Khare et al. reported the ampicillin + cloxacillin combination to be the most prescribed antibiotic for dental problems in a rural setting, albeit without giving any proportion [38].

Antibiotic Use in Different Settings and Populations a. Difference in Antibiotic Prescription Rate between the Urban and Rural Population
Four studies [45,[49][50][51] assessing 2283 prescriptions found the antibiotic prescription rate of dental practitioners in the urban population to vary between 27% and 77%.
Only one study reported the prescription rate in rural population where the prescribers were informal healthcare providers (IHCPs) [38]. This study assessed 1273 prescriptions, of which 88.45% contained at least one antibiotic ( Figure 2).

b. Difference in Antibiotic Self-Medication Rates between Urban and Rural Population
The antibiotic self-medication rate was found to be between 5% and 35% in the urban setting among 862 self-medicating subjects from four studies ( Figure 3) [58,59,64,65]. The rate in the rural setting was reported in one study only, and this was found to be 10% among 120 self-medicating people [63].

c. Difference in Antibiotic Prescription Rate between Adults and Children
The antibiotic prescription rate in adults from three studies [38,45,51] involving 2173 prescriptions ranged from 56% to 88%, whereas that in children was 27% and 67% from two studies [49,50] involving 900 prescriptions.

d. Difference in Prescription Rate Based on Prescriber Characteristics
Five studies compared antibiotic prescription rates for various clinical indications and dental procedures among dental practitioners with and without a postgraduate qualification [69,72,73,82,85].
Overall, 74.9% (SD 21.53) of BDS-qualified dentists and 52.1% (SD 25.6) of MDSqualified dentists prescribed antibiotics for the indications identified (Table 7). An independent sample t-test was used to compare the means between both the groups. The results show that MDS-qualified dentists prescribed statistically significantly fewer antibiotics compared to BDS-qualified dentists (Table 8).

Factors Influencing Practitioners' Prescription Pattern and/or Choice of Antibiotics
The various factors that influenced the prescription pattern of antibiotics were identified from four studies [35,80,83,84]. The most common factors were found to be the cost of the antibiotic and marketing factors, both of which were reported in three studies [31,48,74]. Surprisingly, only 20% of dentists took guidelines into consideration while prescribing antibiotics [68].

Reasons for Self-Medication with Antibiotics among Patients with Oral/Dental Problems
The qualitative study by Ahmed et al. [88] reported the reasons for using antibiotics (as self-medication) among patients with dental/oral problems.
The various reasons that emerged from this study were: 1. avoidance of the dentist; 2.
easy accessibility to antibiotics without prescription and the ability to use these repeatedly as and when there is dental pain; 3.
time constraints and cost of dental treatment; 4.
immediate relief from dental pain, 5.
mutual trust between the pharmacist and customers (dental patients), in the form of credits given by pharmacies to buy antibiotics, the ability of patients to return or replace antibiotics when they do not work.

Discussion
To the best of our knowledge, this is the first systematic review that explores the prevalence of the overuse of antibiotics for dental problems in India, a low-middleincome country which contains one-sixth of the world's population. The key findings show high rates of antibiotic use, both through prescriptions and self-medication, inappropriate prescriptions, both therapeutically and prophylactically, and a readiness amongst the local population to use antibiotics for dental problems without consulting a dental professional. Worryingly, combination antibiotics which are not recommended by the WHO AWaRe classification were commonly used.

Antibiotic Prescription Rate
Our dental outpatient antibiotic prescription rate for adults ranged between 56% and 88%, which is much higher than the maximum accepted proportion of antibiotic prescriptions recommended by the WHO in any outpatient setting, which is 30% [92]. Additionally, the prescription rate for the child population was also high (66%) in Kaikade et al.'s study [50]. Our prescription rate is much higher when compared to 45.8% in England [93] and 57.4% in Germany [94]. This could be attributed to the stricter guidelines that are in place in these two countries. It is important to point out that the antimicrobial guidelines framed by the Indian Council of Medical Research, 2019, has no information on prescribing guidance in dentistry [95].
It is likely that heterogeneity estimations were high (I 2 = 99.53%) due to the small number of studies within objectives. It is also possible that study factors such as location and populations may also contribute to significant heterogeneity; however, due to small sample sizes, we were not able to run subgroup meta-analyses. For this reason, metaanalysis was not performed.

Antibiotic Prescription in Dentistry versus Medicine
Only two of our included studies reported these data, and there was a wide variation between them. In both cases, the prescribers were not exclusively dentists. In the study by Khare et al. [38], dental patients accounted for 8% of all patients visiting IHCPs, but 10% of total antibiotic prescriptions. On the contrary, Chandy et al. [47] reported the antibiotic rate for dental problems as being 3.3% of all prescriptions. This difference could be attributed to the study location, as the former study reported on a rural population and the latter study reported on both rural and urban populations. Whilst these rates are comparable to the figures reported globally [17][18][19][20][21], the results must be taken with caution, as these data were from just two studies, and they also do not account for self-medication.

Self-Medication Rate
Although it is illegal to purchase antibiotics over the counter, we found in this review that self-medication with antibiotics was widely prevalent for dental problems in India. It could be argued that these figures could be much larger than they seem, as a significant proportion of patients who self-medicated did not know the names of the medicines they were taking [60].
Exploring the reasons for self-medication in India, Panda et al. reported that the perception of poor accessibility to healthcare, the chronic nature of disease and having a symptom count of more than two significantly increased the likelihood of using over the counter medication [96]. All of these factors are true with respect to dental disease. The results from our review are comparable with the antibiotic self-medication rates reported in other South East Asian Regions [97]. The rates in Pakistan [98] and Egypt [99] were 5.85% and 19.4%, respectively.
The high heterogeneity percentage (I 2 = 98.80%) made these findings unsuitable for carrying out further meta-analysis.

Indications for Antibiotic Prescription
These data, synthesised from questionnaire studies, showed that dentists prescribed antibiotics for a number of acute and chronic dental conditions that clearly had no indications for antibiotic prescription and where local interventions such as draining the infection, removing the pulp or extracting the tooth would have sufficed. Inappropriate antibiotic prescription is not exclusive to India; it is a global problem and studies have found dentists' poor adherence to antibiotic prescribing guidelines in developed countries [17,19,[100][101][102] as well as developing countries [103].
Dentists reported prescribing prophylactic antibiotics to healthy patients for routine procedures such as scaling, simple extractions, minor surgical procedures and during root canal treatment. Unjustified use was reported in our review in certain medical conditions such as diabetes and hypertension, while in some conditions, routine prescription for dental procedures could be dangerous, as in the case of pregnancy and liver damage. Although the most common reason for prescribing prophylactic antibiotics was the prevention of infective endocarditis, our results show that dentists had poor knowledge of the guidelines. Furthermore, all our included studies were found to be published after 2007 AHA guidelines, but patients with prosthetic heart valves, mitral valve prolapse without regurgitation, congenital cyanotic heart diseases, myocardial infarction, pacemakers, and surprisingly rheumatoid arthritis were still prescribed prophylactic antibiotics for routine dental procedures when they should not have been. Again, this was similar to global trends [22,28].
The studies included in the review that assessed specific indications for prescription were obtained from self-reported questionnaire surveys. This type of study design introduces social desirability bias. The fact that respondents could have given answers that they believe as favourable could have led to our results being underestimates. Self-reporting, whether by providers or patients, always carries the risk of bias, however strong the study design is.
This review identified several non-clinical reasons including fear of losing patients, time constraints, training skills (unsure diagnosis, incomplete treatment), pressure from the patient on one side and market pressure from pharmaceutical companies on the other as leading dentists to prescribe antibiotics outside clinical indications. A recent umbrella review on the global population identified similar factors associated with antibiotic prescribing in acute dental conditions, including a "just in case" approach to prevent serious complications, peer influence, pressure from patients and impact of workload [23].
In this review, we found that a significant number of knowledge-based studies were conducted in tertiary care teaching institutions among teaching faculty with specialist qualifications. This could indicate a lack of knowledge among the trainers, which in turn calls into question the quality of the education passed on to the dental students regarding the appropriate use of antibiotics for dental diseases. Although some of our studies found that antibiotic prescription rates for specialist qualified dentists (MDS) were significantly lower compared to general dental practitioners (BDS), it must be emphasised that awareness regarding appropriate antibiotic prescription must begin in undergraduate training, and future interventions thus need to target undergraduate curricula to align them with current guidelines and antimicrobial stewardship in dentistry.

Types of Antibiotics
A total of 32 different prescribing patterns were identified. A number of them belonged to the WHO Watch category, which includes some critically important antibiotics that have a higher resistance potential [41].
The WHO discourages the use of fixed dose combinations of multiple broad-spectrum antibiotics, as it is not evidence-based. Seven out of nine antibiotic combinations identified in our study fell under this "not recommended" group. Moreover, over a quarter of antibiotic prescriptions in our review contained a fixed dose drug combination (FDC). The total antibiotic sales in India rose by 26% between 2007 and 2017, and FDCs contributed a major share to this, comprising a 38% increase, compared to a 20% increase in single drug formulations [104]. While FDCs help with treatment adherence in case of certain prevalent illnesses in India such as tuberculosis, malaria and HIV infection [105], their use for dental problems, especially in such high proportions, is not justified.
Although amoxicillin was the most popular therapeutic antibiotic in our review, similarly to previous studies on other populations [30,94], the use of broad-spectrum amoxicillin + clavulanic acid was also common among dentists in India. This is in contrast with the studies carried out in England and Germany, where amoxicillin+ clavulanic acid accounted only for 0.5% and 4.2%, respectively [30,94], of all antibiotics prescribed in dentistry. A recent systematic review on the global population identified both amoxicillin and amoxicillin + clavulanic acid to be popular therapeutic antibiotics in dentistry, similar to our review [106]. The increased use of broad-spectrum antibiotics could be attributed to their increased availability. The number of pharmaceutical companies manufacturing higher generation cephalosporins and amoxicillin + clavulanic acid was greater than the number of companies that manufacture amoxicillin [107]; in fact, only one company manufactured penicillin and benzathine penicillin [107].
While the consumption of broad-spectrum antibiotics, in general, is high in India [107], there has also been a rapid rise in the consumption of third-generation cephalosporins (WHO Watch category). Meanwhile, in contrast, the consumption of penicillins (WHO Access category) has remained stable [107]. Interestingly, the cost of some cephalosporins was found to be lower than that of Access group amoxicillin [107].

Providers
In all except two studies, the providers were found to be dentists. One study involved pharmacists dispensing antibiotics to standardised patients, and the other study involved informal healthcare providers in rural areas. The latter one had the highest reported antibiotic prescription rate of about 90%, calling into question their role in dental management. In developing countries such as India, the informal sector accounts for 51-96% of all providers and 9-90% of healthcare utilisation, especially for the poor population [108,109]. However, the quality of care has been found to be variable, and these providers were found to lack good knowledge, training or drug provision abilities, and their clinical practice often trailed behind with regard to knowledge [108].
In areas where dentists were not available or accessible, dental management often falls to non-dental providers such as IHCPs and general medical practitioners who are not trained to perform dental procedures, and therefore often tend to resort to antibiotics when patients present to them, especially with acute dental problems. As an untreated dental disease is chronic, patients are forced to take medication over and over again, until they are able to see a dental practitioner.

Role of Pharmacists
In developing countries, especially India, which is the second most populous country in the world, pharmacists are often approached by people for health advice, including dental advice. Shet et al. found that as high as 67% of private sector pharmacies in India dispensed antimicrobial drugs without prescriptions [110]. The reasons cited were convenience and easy access, cheaper cost, availability of credit and difficulty in getting an appointment with a dentist or physician [111]. It is understandable that in India, and other low middle-income countries, a significant proportion of the population may not be able to afford paying a qualified practitioner in addition to paying for medication. A questionnaire study involving pharmacists in India [111] showed that 22.4% of pharmacists would dispense antibiotics for toothache without a dentist's prescription, as compared to 13% in Saudi Arabia [112]. The reason for the difference could be attributed to the economic differences and location of the study population.
This systematic review highlights various areas of antibiotic misuse in India namely inappropriate prescription, i.e., use of Watch category and combination antibiotics, the "just in case" approach of prescribing for dental conditions where antibiotics are not required, routine antibiotic use as prophylaxis in patients with medical conditions, and use in nonclinical situations; antibiotics dispensed by unqualified providers such as pharmacists and informal healthcare providers, and over-the-counter availability and use by the general population for dental problems.

Limitations
The main limitation of this review is the quality of the included studies. The overall quality of individual studies was low to moderate. All the included studies, except one, were cross sectional in nature and were prone to selection bias and confounding factors. Furthermore, as most studies involved questionnaires exploring self-reported knowledge and practice of prescribers, they are prone to social desirability bias, although the direction of this bias may be an underestimation of the extent of the existing problem, particularly in those who are aware of antimicrobial guidelines. That said, we used the studies only to provide descriptive data (percentages). We did not combine data from the studies to undertake meta-analysis, which would have been affected by the study quality, as well as the heterogeneity.

Future Research and Clinical Implications
This systematic review gives sufficient evidence that there is a substantial problem of overuse of antibiotics for dental problems in India, with antibiotics being prescribed inappropriately for clinical and non-clinical reasons; inappropriate, potent and combination antibiotics being prescribed; and antibiotics being obtained over the counter for dental problems by the general population. The review establishes the difference in antibiotic prescribing rates between general dentists and specialist qualified dentists, highlighting the need to emphasise the importance of optimal antibiotic prescribing in dental training.
A combination of factors including (i) provider issues such as a lack of knowledge, attitude, training, gaps in knowledge and practice, (ii) patient issues such as awareness and beliefs and (iii) policy issues such as guidelines, pharmacy regulations need to be addressed to bring about meaningful stewardship programmes. Further qualitative research is needed focussing on specific areas, for example, providers, the teaching faculty, pharmacists, policy makers or patients, to understand their knowledge, beliefs and barriers to antibiotic use and misuse. There is also a need to develop anti-microbial stewardship programmes to enable providers to appropriately prescribe, and patients to avoid self-medication.

Conclusions
Antibiotic misuse in dentistry is a serious global threat, with inappropriate use by both dental and non-dental healthcare professionals in India. The use of combination antibiotics and self-medication for dental problems was also alarming. Considering the serious problem of antibiotic resistance, there is an urgent need to address this overuse of antibiotics for dental/oral problems in India, using interventions that are targeted at both healthcare professionals and the general public to enable a nationwide change in this area.   Data Availability Statement: Data will be made available upon reasonable request to the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.