Addressing Antimicrobial Resistance in Dentistry Manjunath BC1, Chandrashekar BR2, Vatchala RRM3, Babaji P4, Singh I5, Arora K6, Madan C7

Journal of Oral Health REVIEW ARTICLE Community& Dentistry

ABSTRACT Background: Antimicrobial agents are life saving drugs which are used in management of various life threatening infections but irrational use of antibiotics have led to resurgence of multidrug resistant bacteria which are associated with global increase in mortality due to various infections. Dentists are one among important health care personnel who prescribe antibiotics routinely to treat various oral infections. Objectives: To summarise the evidence of antimicrobial resistance (AMR) encountered in dental practice, discuss factors associated with it and suggest measures to prevent antimicrobial resistance in dentistry. Methodology: Articles were identified by searching in electronic data bases such as PubMed, Medline, Embase, Google Scholar and Cochrane data bases using key words like antibiotics, antimicrobial resistance, and antibiotic resistance in dentistry. The articles fulfilling the objectives were included. Results and Conclusions: Dentists also contribute significantly to the global burden of antimicrobial resistance due to irrational use of antibiotics. Antibiotic stewardship is essential to prevent antimicrobial resistance in dental practice and hence there is an urgent need to educate not only dentists but general public as well. The article describes the gravity of the AMR and the importance of prudent use of antibiotics is discussed.

Keywords: Antibiotics, Antimicrobial, Resistance, AMR, Antibiotic stewardship, NDM-1, Superbug, MRSA

INTRODUCTION 1Senior Professor and Head 5Senior Lecturer Department of Public Health Dentistry Department of Public Health Dentistry he accidental discovery of a mould Post Graduate Institute of Dental Sciences, Government Dental College, Srinagar, Jammu called “Penicillium Notatum” Rohtak, Haryana, India and Kashmir, India which had the potential of inhibit- 2 6 T Associate Professor Associate Professor ing Staphylococcus colonies by Alexander Department of Public Health Dentistry Department of Periodontics and Implantology Flemming in 1928 paved the way for the People’s Dental Academy, Bhanpur, Bhopal, MP, Manav Rachana Dental College and Hospital, India Faridabad, India miracle drug “Penicillin” which saved mil- lions of lives and opened a new era of 3Senior Lecturer 7 Senior Lecturer Department of Oral Pathology and Microbiology Department of Periodontics and Implantology curative medicine (1).Penicillin is referred Faculty of Dentistry, Jamia Millia Islamia, ESI Dental College, Rohini, New Delhi, India as the mother of all antibiotics and the New Delhi, India discovery proved to be a boon to man- 4Reader kind. There are various generations of an- Department of Pedodontics and Preventive Dentistry, Vyas Dental College & Hospital, tibiotics at present which are effective Jodhpur, Rajasthan, India against wide spectrum of microbes but at the same time many microbes have developed resistance even to last known genera- Contact Author tion of antibiotics and threatening to push Dr. Manjunath BC us to the pre-antibiotic era. [email protected] The resistant microbes become super bugs and the discovery of New Delhi Metallo J Oral Health Comm Dent 2013;7(2)101-107

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β-lactamase-1 (NDM-1) in India by available higher generation of antibiotics community participation, weak or absent Kumarswamy KK et al. in 2010 (2) has where in, it will be difficult to control vari- monitoring systems, availability of poor brought back the issue of antibiotic resist- ous life threatening infections and hence quality medicines, misuse of antibiotics, ance in to spotlight. Recent report sug- all health care practitioners, policy makers, poor infection control protocols in the gests that this super bug (NDM-1) is not patients should be aware about this stark hospitals, low level of accessibility to diag- only confined to some of the hospitals in reality and work together in a coordinated nostics, medicines and vaccines along with India but in drinking water of New Delhi manner to save the life saving antibiotics insufficient research efforts for the devel- as well (3). The newly discovered super bug for our future generations also. opment of new generation of drugs (8,9). NDM-1 is actually an enzyme which gets transmitted to gram negative organisms This article provides evidence regarding re- ANTIBIOTIC RESISTANCE IN INDIA like Escherichia coli and Klebsiella sistance of various oral micro organisms Indian subcontinent is perceived as a hot pnuemoniae which are resistant even to to wide spectrum of antimicrobial drugs, bed for resistant microbes and a plethora carbapenem group of drugs (2,3). A wide explains factors affecting prescription of of factors are responsible such as irrational variety of gram negative microorganisms antibiotics among dentists and suggests prescription of antibiotics by health care are present in oral cavity which are associ- guidelines to prevent antibiotic resistance practitioners like prescription of antibiot- ated with periodontal diseases and if in dentistry. ics for viral infections, advising NDM-1 enzyme gets transmitted to them, antimicrobials without a culture and sensi- then there may be catastrophic consequences ANTIMICROBIAL RESISTANCE tivity report, use of higher generation of in the oral cavity and hence as dentists, we (AMR) antibiotics, increased pressure to prescribe should be updated regarding current sce- Antimicrobial resistance (AMR) is a fast newer antibiotics, self medication and of- nario and prevent superbugs in the oral emerging global public health problem and ten non-compliance of full course of anti- cavity. can be defined as resistance of a microbial biotics by patients, availability of antibiot- agent against an antimicrobial drug to ics over the counter (OTC), poor quality It is not only the problem of the which it was susceptible before. AMR is of the drugs, coupled with primitive infec- superbugs but many microbes which cause the result of misuse of antimicrobial medi- tion control in hospitals and weak or defi- life threatening infections like tuberculo- cines and develops when a microorganism cient sanitation (10,11). It is also com- sis, malaria, influenza, pneumonia, and mutates or acquires a resistance gene (8). pounded through weak surveillance sys- viruses like HIV have become resistant to tems and non-availability of antibiotic standard and even to combination of an- MECHANISM policy at the national level but now India is timicrobial drugs. The problem is further Development of resistance to drugs by all set to see its first antibiotic policy being compounded by Methicillin-resistant Sta- microorganisms is a natural phenomenon passed by the central government very soon phylococcus aureus (MRSA), pathogenic co- but is enhanced by irrational use of which is a positive step in tackling antimi- agulase negative staphylococcus aureus and antimicrobials. Naturally resistant strains crobial resistance (12). Vancomycin resistant enterococci (VRE) (4). and those which have acquired resistance, emerge due to selective pressure exerted by ANTIBIOTIC USE IN DENTISTRY Even though, World Health Organisation exposure to antimicrobial drugs. The ge- Dentists account for approximately 7-11% (WHO) had warned about the threat of netic information is passed on through of all antibiotic prescriptions in the world antimicrobial resistance as early as 2000 (5), horizontal gene transfer between microbes (13-17). Although, the percentage is less it was neglected in aftermath of 9/11 but which allow resistance determinants to when compared to medical practitioners, at present we are staring at an impending spread within harmless environmental or antibiotics are one among frequently pre- deep public health crisis and realising its commensal microorganisms and patho- scribed drugs which significantly contrib- impact on mankind, World Health Organi- gens, thus creating a reservoir of resistance. utes to national and or global patient con- sation (WHO) has dedicated the theme of Resistance is also spread by the replication sumption of antibiotics and hence a mat- World Health Day 2011 to combat drug of microbes that carry resistance genes, a ter of deep concern (13, 14). The rate of resistance with a slogan of “No action to- process that produces genetically identical resistance development may be delayed if day; No cure tomorrow (6).” (clonal) progeny (9). dentists, along with other health care practitioners use antibiotics more judiciously. Dentists prescribe antibiotics for treating FACTORS AFFECTING ANTIBIOTIC In dental practice, antibiotics are invaluable various oral infections and reports high- RESISTANCE adjuncts in treatment of oro-facial infec- light that many oral microbes have devel- According to World Health Organisation, tions which are usually prescribed for man- oped resistance to wide variety of antibiot- the antimicrobial resistance is a multifacto- agement of acute odontoge-nic infections, ics largely due to irrational use (7). At the rial problem and can be summarized due non-odontogenic infections, as prophylaxis present rate of antimicrobial resistance to deficient antimicrobial policies and against focal infection in patients at risk (AMR), we are at the risk of utilising all the guidelines at the national level, inadequate (en-docarditis and joint prosthesis), as

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prophylaxis against local infection and sys- like S. sanguis, black-pigmented Prevotella ceptible to amoxicillin+clavulanic acid temic spread (14,15). and nonpigmented Prevotella were resist- (32,34). It is evident that many oral patho- ant to amoxicillin, ampicillin, cefazolin and gens are susceptible to this combination Epstein JB et al (16) reported that the sam- cefotaxime (23,24). β-lactamase production (35) and hence it should be used exclusively pled dentists in British Columbia, Canada have also been detected in some species of for treatment of â lactum resistant infec- prescribed an average of 4.45 antibiotics Clostridia, Fusobacteria, Prevotella, tions and that too after confirming through prescriptions per week after treatment which Porphyromonas and in some other anaero- culture and sensitivity tests. were primarily penicillin and its derivatives. bic bacteria (25). Similarly Mainjot A et al (17) have reported LINCOSAMIDES a median number of prescriptions per den- Since amoxicillin is prescribed by dentists Clindamycin, a broad-spectrum antibiotic tist to be 3 per week among Belgian den- than any others, it may lead to emergence with activity against aerobic, anaerobic, and tists. 82% of all prescriptions were for of resistant strains (16,17). It has been con- β-lactamase-producing pathogens is used amoxycillin, amoxycillin-clavulanic acid and firmed by many studies in which a total of as second line of drug after penicillin and clindamycin. 224 amoxicillin-resistant bacteria were iso- cephalosporins which may be useful in lated which belonged to Haemophilus spe- penicillin-allergic patients but should be DEVELOPMENT OF RESISTANCE cies, Streptococcus species, and Veillonella used after confirmation by culture and sen- AMONG ORAL MICROBES species. This study has demonstrated that sitivity tests. Clindamycin has been used The oral cavity is colonised by a diverse a diverse collection of amoxicillin-resistant for many years as prophylactic treatment range of microbial flora which comprise bacteria is present in oral cavity (26). Pres- during dental procedures to prevent endo- of more than 700 species of bacteria, fungi ence of amoxicillin resistant organisms carditis (36). Even though, resistance to and protozoa, of which only 10% are regu- (ARO) isolated from dental plaques adds clindamycin has been reported in larly isolated using conventional culture furthermore evidence to AMR (27,28). Porphyromonas gingivalis and Bacteroides techniques (18,19). ureolyticus (37), it still has a strong antimi- Various generations of cephalosporins are crobial activity on anaerobes. DEVELOPMENT OF RESISTANCE BY used as an alternative to amoxicillin in den- ORAL MICROBES TO VARIOUS tistry as they are less allergenic, have de- MACROLIDES ANTIMICROBIAL AGENTS creased toxicity risks, added with broad The macrolides which include erythromy- ß-LACTAMS spectrum of activity. It is the latter feature cin, azithromycin, and clarithromycin are β- lactum antibiotics are commonly used however, that encourages the selection of not routinely used in dental practice as they in dental practice which include penicillins, microorganisms that are resistant to these are bacteriostatic and cannot be used in cephalosporin and related compounds are drugs (29). acute infections (38). Azithromycin is less active against many gram-positive, gram- effective against gram-negative Cocci than negative and anaerobic organisms but be- Many strains of oral bacteria like Prevotella erythromycin (39). The findings of a study comes ineffective due to production of β- denticola and Streptococcus viridans are reveal that erythromycin is ineffective against lactamases by certain strains of bacteria (20). resistant to fourth generation of cepha- Streptococcus viridans and most of Fuso- Streptococcus viridans which is associated losporin (30). Increased rates of resistance bacterium species (24) and also has de- with bacterial endocarditis is resistant to to cephalosporins such as ceftriaxone, creased activity against non pigmented Penicillin G and also β- lactamase produc- ceftazidime, cefpirome and cefepime have Prevotella (22). A recent study suggested ing Prevotella species and hence choice of been reported among Streptococcus that Streptococcus oralis and Streptococ- other effective antibiotic is necessary (21). viridans in neutropenic cancer patients (31). cus mitis have developed resistance to macrolide group of antibiotics (40). Amino-penicillin group are one among β- LACTAMASE INHIBITORS main antibiotics used routinely in dental The inactivation of amoxicillin by β- TETRACYCLINE practice which include amoxicillin and ampi- lactamases of gram negative anaerobic bac- Tetracycline is a broad-spectrum antibiotic, cillin (16,17). Report suggests that many teria can be prevented by the addition of â- used as an adjunct to mechanical periodon- oral microbes have developed resistance to lactamase inhibitors such as Amoxicillin + tal therapy. Due to its irrational use in man- these drugs which may be associated with Clavulanate, Ampicillin + Sulbactam, agement of periodontal infections, many past history of administration of β-lactams Piperacillin + Tazobactam and Ticarcillin + oral microorganisms have developed re- hence β-lactamase stable antibiotics should Clavulanate (32,33). sistance (41). Tetracycline-resistant bacteria be prescribed to patients with unresolved have been isolated from oral microbial flora infections who have received â-lactams ear- β - lactamase inhibitors are often used in in which most of the isolates carried tetra- lier (22,23). recurrent oral infections. It has been found cycline resistance genes out of which, the that many periodontal pathogens like P. most common gene identified was tet(M), It has been reported that micro organisms gingivalis and P. intermedia are highly sus- followed by tet(W), tet(O), tet(Q) and

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tet(S) (42). The tet(M) containing strains that is levofloxacin. The oral pathogens such that long term use of antiplaque agents was predominantly present in strains of as Streptococcus viridans, P. gingivalis and available in dentifrices and mouth rinses Streptococci, mainly S. intermedius, S. Prevotella species demonstrated resistance does not lead to selection of resistant oralis and S. sanguis. It was also detected (21,37). strains or significantly affect the structure in Actinomyces, Bifidobacterium, and of microbial oral flora. There is also no Veillonella species, Prevotella and Bacter- ANTIFUNGALS evidence of colonization of pathogenic or oides isolates (43,44). Newer strains like The incidence of oral candidiasis is increas- opportunistic microorganisms and hence Streptococcus parasanguinis and Eubacte- ing in the world largely due to HIV infec- can be used daily for prevention of peri- rium saburreum are also reported to be tion where in a combination of antimicro- odontal diseases (55,56). resistant to tetracycline (45). Since tetracy- bial drugs are used to manage variety of cline is used both in systemic as well as in infections arising due to immuno-compro- CHLORHEXIDINE MOUTH RINSES local drug delivery systems, it enhances se- mised state. Due to this, Candida albicans Chlorhexidine gluconate is still considered lection to these agents by oral microbes has developed resistance to azole group of a gold standard for antiplaque mouth and hence decision to use antibiotics antifungals. Resistance has been observed rinses, which is used for short duration should be based on the merit of individual to amphotericin B, nystatin, cotrimazole, after periodontal therapy. The development case. fluconazole which makes the dentists left of resistance is probably less compared to with very little option due to which prog- antibiotics or biocides containing quater- NITROIMIDAZOLES nosis becomes poor. The multidrug resist- nary ammonium compounds (57) but still The nitroimidazole group of drugs is spe- ance of C. albicans is due to MDR-1 and resistance of Streptococcus sanguis has been cifically anti-anaerobic in nature which in- CDR-2 genes (50-52). reported against chlorhexidine (58). Due cludes metronidazole, nimorazole, to limited number of investigations, it is tinidazole and ornidazole which has been CARBAPENEMS difficult to arrive at a conclusion but never- proved to be efficacious in treating acute Carbapenem is the last group of antibiot- theless chlorhexidine should be prescribed ulcerative gingivitis, chronic progressive ics which include drugs like meropenem, only for a short duration to prevent ad- periodontitis, pericoronitis, periapical in- imipenem and faropenem, are usually re- verse effects associated with long term us- fections, osteomyelitis and dry socket served for the life threatening infections. age and also the risk of resistance. where anaerobes are implicated as patho- Even though report suggests that all oral gens (46). Serrano C et al (47) isolated eleven microbes are susceptible, it should not be TRICLOSAN MOUTH RINSES species which included Fusobacterium considered because of risk of development Triclosan is a biocide, widely used in mouth nucleatum, Prevotella intermedia and of resistance (30,37). In a few conditions rinses, dentifrices, cosmetics and common Prophyromonas gingivalis which were re- like children undergoing treatment for can- household products which enhance the risk sistant to metronidazole. Aggregatibacter cer, meropenem resistance among alpha- of selection of less susceptible organisms actinomycetem comitans and hemolytic streptococci was observed (53). (59). Triclosan mouth rinse is favoured over Porphyromonas gingivalis which are causa- chlorhexidine due to its decreased side ef- tive organisms of periodontitis are associ- RESISTANCE OF ORAL MICROBES fects but rapid widespread daily use of ated with resistance to metronidazole along TO ANTISEPTIC MOUTH RINSES triclosan in many forms may present a po- with amoxicillin and clindamycin (34). Many AND DENTIFRICES tential public health risk in regard to devel- Oral anaerobes are still susceptible to met- Dentifrices and mouth rinses contain thera- opment of resistance. Even though, there ronidazole (35) hence judicious use of it is peutic agents which are effective in prevent- is no scientific evidence regarding the use necessary in management of periodontal ing dental plaque and controlling gingival of triclosan mouth rinses and bacterial diseases. inflammation. Even though, dentifrices are resistance, but considering the fact that it is used daily, there is less chance of develop- used widely in many cosmetic products, FLUOROQUINOLONES ment of resistance by oral bacteria. The daily mouth rinsing with triclosan should Ciprofloxacin is one of the antiplaque or antiseptic formulations which be limited to only special cases who are fluoroquinolone group of antibiotics contain chlorhexidine, triclosan, cetylpyrid- unable to perform mechanical oral hygiene which can be used in combination with inium chloride, sodium benzoate, povi- practices and patients who are immuno- metronidazole for the treatment of mixed done-iodine, hydrogen peroxide and es- compromised (60,61). anaerobic periodontal infections when the sential oils are topically used as mouth patient has an allergy to beta-lactam antibi- rinses. They are bactericidal when used un- PREVENTION OF ANTIMICROBIAL otics (48). Findings of an in vitro study diluted and bacteriostatic if diluted with RESISTANCE IN DENTISTRY reported that F. nucleatum and P. gingivalis water. Since, chemical antiplaque agents are Dentists can make a difference by using exhibited resistance to ciprofloxacin (49). topical in nature and often mixed with water antimicrobials judiciously by prescribing Antimicrobial activity is also reported in 2:1 ratio, the risk of development of correct antibiotic regimen only when indi- against third generation of fluroquinolones resistance is low (54). It has been reported cated; keeping a track record of the pre-

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scribed antibiotics and signs of resistance tives to promote rational use of antibiot- Obtaining thorough knowledge of the among patients must be identified and ics in dentistry can be organised at the local, side effects and drug interactions of an documented. The practice of prudent use national and at international level. Regular antibiotic before prescribing it. of antimicrobials is referred as “Antimi- workshops and continuing dental educa- Educating patients regarding proper crobial stewardship” and can be put in to tion programs (CDE) to update the knowl- use of antibiotics and stressing the practice when they prescribe for antibiotic edge on application of antibiotics should importance of completing full course prophylaxis and for therapeutic purposes be initiated on priority basis (70). of therapy. (62). Generic drugs are as effective compared GUIDELINES OF RATIONAL USE OF to branded ones which also reduce cost. ANTIBIOTIC PROPHYLAXIS ANTIBIOTICS IN DENTISTRY Prophylactic antibiotics are prescribed to Indications (15, 71, 72) Control of antimicrobial resist- prevent metastatic spread of pathogenic Evidence of systemic spread ance through inter-sectoral oral bacteria leading to infections such as Facial cellulitis and / or dysphagia coordination (9) infective endocarditis (63). According to a Aggressive periodontitis Responsible actions are to be taken to en- Cochrane systematic review, there remains Necrotising ulcerative periodontal dis- sure appropriate use of antibiotics where no evidence, whether penicillin prophylaxis eases ever necessary such as at the local, national, is effective or ineffective against bacterial Pericoronitis and international levels. endocarditis in people at risk who are about Acute periodontal conditions where Improvement of diagnostic services to undergo an invasive dental procedure drainage is impossible through capacity building measures (64). Antibiotic prophylaxis is essential in Space infection of the head and neck particularly in developing countries. some of the conditions and it is advised after pus drainage Development of standard infection to follow updated recommendations of In acute situations of odontogenic in- control protocols in all health care set American dental association (ADA) and fection of pulpal origin but as a com- ups. American heart association (AHA) (65,66), plement to root canal treatment Practice of antibiotic stewardship to prevent antibiotic resistance in cardiac among all health care practitioners in- conditions and guidelines of American When antibiotics are not required cluding veterinarians. association of orthopedic surgeons (15,72) Education and motivation of the pub- (AAOS) in patients with total joint replace- Chronic marginal gingivitis lic regarding proper antibiotic use. ments (67). Guidelines of the respective Chronic periodontitis Building and enhancing surveillance countries should also be considered if avail- Dry socket programs; able. Irreversible pulpitis with or without Financial resource mobilization to un- acute periapical periodontitis dertake research activities with regard THERAPEUTIC PRESCRIPTIONS Necrotic pulp with or without acute to developing new drugs. Many studies conducted among dentists periapical periodontitis Regulating over the counter sale of in Belgium (17), Australia (68), Kuwait Necrotic pulp with chronic periapical antibiotics and central prescribing re- (69), suggested over use or misuse of anti- periodontitis without swelling strictions along with advertising curbs. biotics which were associated with poor Necrotic pulp with a draining sinus tract International cooperation and assist- understanding of pathological processes ance. involved in pulp and periapical diseases, General Principles (73,74) Controlling and improving the quality lack of knowledge regarding indications for Making an accurate diagnosis. of generic antibiotics. effective antibiotic use, whenever there is Using appropriate antibiotics and uncertainty of diagnosis, for convenience, proper dosing schedules. CONCLUSIONS expectation of patient and lack of time to Considering narrow-spectrum antibac- Antimicrobial therapy is an invaluable and treat immediately. There is lack of uniform- terial drugs in simple infections to mini- life-saving adjunctive therapy but inappro- ity in the rationale for antibiotic use among mize disturbance of the normal priate and indiscriminate use, has led to dental practitioners and this can be solved microflora, and preserve the use of wide-spread development of multidrug by formulation of guidelines by national broad-spectrum drugs for more com- resistant strains which are associated with dental associations. The formulation of plex infections. increased mortality in the world. Dentists evidence-based guidelines will prevent mis- Using a loading dose to rapidly achieve are one among the global prescribers of use of antibiotics by dentists which has therapeutic blood levels. antibiotics, so prudent and judicious use become a global problem (69). Avoiding combinations of bacterio- of antibiotics among them is necessary for static and bactericidal drugs. combating bacterial resistance. There is an Creating awareness among dentists is of Avoiding unnecessary use of antibac- urgent need to formulate guidelines for utmost importance and educational initia- terial drugs in treating viral infections. treatment and educational initiatives to

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