CONTINUING EDUCATION IN HONOR OF NORMAN TRIEGER, DMD, MD

Antimicrobial Drugs

Daniel E. Becker, DDSAssociate Director of Education, General Dental Practice Residency, Miami Valley Hospital, Dayton, Ohio

Antibiotics play a vital role in dental practice for managing orofacial infections. Theyare used to manage existing infection and they are also used as prophylaxis forcertain medical conditions and surgical procedures. This article will reviewpharmacological and therapeutic considerations for the proper use of these agentsfor dental infections.

Key Words: Antibiotics; Antifungals; Dental infections; Antibiotic prophylaxis.

An astounding number of drug classes and formula-tions are available to manage infections. Fortu-

nately, the microorganisms associated with odontogenicand periodontal infections are well characterized and arelatively small number of antimicrobial agents are requiredto effectively manage dental infections. With the exceptionof allergy, adverse effects attributed to these antibiotics aresurprisingly infrequent, but most agents are implicated inproducing nausea, dyspepsia, and diarrhea. This articlewill review essential pharmacology of appropriate drugclasses and then address clinical considerations for theirtherapeutic and prophylactic use.

PHARMACOLOGICAL CONSIDERATIONS

Antibiotics are generally classified according to theirmolecular structure and their antimicrobial mechanisms.Ideally, these mechanisms of action either interruptsynthesis of structural components or alter specificmetabolic functions that are unique to microbial cells.Such specificity cannot always be accomplished, but if itis, human cells can be spared cytotoxic effects.

Beta Lactam Derivatives

The molecular structures of penicillins and cephalospo-rins have a beta lactam ring in common that accounts for

their ability to inhibit cell wall synthesis in susceptiblemicroorganisms1 (Figure 1). Additional beta lactamderivatives include the monobactams and carbapenems,but these are not used for dental infections. The betalactam ring is also the target for resistant species, whichproduce a variety of beta lactamases formerly calledpenicillinase and/or cephalosporinase. Prominent mi-crobial species that produce beta lactamases areStaphylococcus aureus and Haemophilus influenzae.However, several species of Bacteroides and Prevotel-la, which contribute to the more severe odontogenic andperiodontal infections, may also demonstrate this mech-anism of resistance.

The similar molecular structure for penicillins andcephalosporins raises concern regarding cross-allerge-nicity. Formerly this was thought to be related to the betalactam ring, but recent evidence has established thatcross-allergenicity is related more to similarities in the Rside chains2,3 (see Figure 1). It is generally accepted thatpatients having a history of IgE-mediated reaction to apenicillin should be managed using a non–beta lactamantibiotic.4 Urticaria (hives) is immunoglobulin E medi-ated but accounts for only 10% of all exanthematousdrug reactions. The overwhelming majority of cutaneousreactions to penicillins are pruritus or rash; these are notimmunoglobulin E mediated, and any potential for cross-reaction is unlikely.5,6 Furthermore, upon further ques-tioning, most patients claiming allergy to penicillin arediscovered to have experienced stomach upset (dyspep-sia), nausea, or diarrhea. Although macrolides andclindamycin are conventionally considered the alterna-tives of choice in patients allergic to penicillins, the

Received March 30, 2013; accepted for publication May 20, 2013Address correspondence to Dr Daniel E. Becker, Associate

Director of Education, General Dental Practice Residency, MiamiValley Hospital, One Wyoming St, Dayton, OH 45409; debecker@mvh.org.

Anesth Prog 60:111–123 2013 ISSN 0003-3006/13� 2013 by the American Dental Society of Anesthesiology SSDI 0003-3006(13)

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macrolides have become less attractive and will bediscussed further below. It is preferable to substitute analternate penicillin or cephalosporin for a penicillin-allergic patient, provided the nature of the patient’sreaction was merely pruritic (itch) or a maculopapularrash. A history of urticaria (hives) or anaphylactoidsymptoms is more convincing evidence that the patient’sreaction to penicillin was truly immunoglobulin Emediated, and in this case, one should refrain fromprescribing any beta lactam derivative. Clinical manage-ment of the penicillin-allergic patient is summarized inFigure 2.Penicillins. The fortuitous discovery of penicillin is

credited to Alexander Fleming, and its clinical use beganin 1941 This first penicillin was designated penicillin Gand its dosage expressed in units or milligrams, 1600units approximating 1 mg. It is very active against gram-positive cocci that frequently cause oral, pharyngeal, andpulmonary infections. It is also active against Neisseriagonorrhoeae and Treponema pallidum. For thisreason, penicillin G is still a first-line agent for treatingthe 2 most familiar venereal diseases, syphilis andgonorrhea. Penicillin G is highly degradable in gastricacid and is generally administered only by parenteralroutes, formulated as several salts that differ in their rateof absorption. Potassium and sodium salts are used forintravenous administration and procaine or benzathinesalts for intramuscular injection. Benzathine formulationsprovide low serum levels for 3–4 weeks and are generallyreserved for situations in which patient compliance withoral administration is unlikely.The phenoxymethyl derivative of penicillin, designated

penicillin V, is more acid stable and has become thestandard penicillin for oral use. Its spectrum is similar tothat for penicillin G, but it is less active against Neisseriaspecies and several anaerobes. It remains the agent ofchoice for mild to moderate intraoral infections but issusceptible to a variety of beta lactamases produced bymost strains of S aureus and many species ofBacteroides.7 Although the former are seldom causativeagents in oral infections, resistant strains of Bacteroidesrepresent a significant cause for penicillin failure. Thisincludes several species of Bacteroides that have been

reclassified as other genera, either Porphyromonas orPrevotella.

To counter microbial resistance attributed to betalactamase, derivatives of penicillin have been synthesizedthat are not susceptible to enzymatic breakdown. Thesepenicillinase-stable agents include oxacillin and dicloxa-cillin. They are primarily indicated in the management ofinfections attributed to S aureus, over 90% of which areresistant to penicillin G and V. These microbes are rarelyif ever present in odontogenic infections, and bothoxacillin and dicloxacillin are less active than penicillin Vagainst odontogenic pathogens.

Ampicillin was the first derivative to have an extendedspectrum that includes several gram-negative organismssuch as H influenzae and Escherichia coli, but these arerarely, if ever, associated with intraoral infections. Apossible exception may be infections that also involve themaxillary or nasal sinuses in which H influenzae is acommon culprit. Amoxicillin has the identical spectrumof activity attributed to ampicillin, but it exhibits greateroral bioavailability, and for this reason ampicillin isgenerally reserved for parenteral use. The bioavailabilityof amoxicillin is also superior to that of penicillin V andaccounts for its replacing penicillin V in currentAmerican Heart Association guidelines for the prophy-laxis of infective endocarditis.

Amoxicillin and penicillin V are equally active againststreptococci. The only advantages of amoxicillin fordental infections are greater bioavailability and a longerhalf-life. For this reason, if one adheres to the principleof choosing antibiotics having the narrowest spectrumpossible, penicillin V is preferred over amoxicillin.Routine use of amoxicillin fosters the accumulation ofamoxicillin-resistant microorganisms that lack dentalimplications. However, if one considers that the leadingcause of therapeutic failure is lack of patient compliance,superior bioavailability and less frequent dosing (3 times

Figure 1. Beta lactam structure. Penicillins and cephalosporinscontain a beta lactam ring (asterisk) that conveys theirantimicrobial action and is the target for microbial resistance.

Figure 2. Managing penicillin-allergic patients.6

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daily [TID] versus 4 times daily [QID] for penicillin V)favor the use of amoxicillin.

Ampicillin and amoxicillin are not beta lactamasestable and are available in formulations that include so-called beta lactamase inhibitors, sulbactam and clavulanicacid respectively. Clavulanic acid has a molecularstructure similar to that of penicillin and has weakantimicrobial action but strong affinity for beta lacta-mase. It is combined with amoxicillin to act as a ‘‘suicidemolecule’’ protecting it from beta lactamase (see Figure3). The combination of amoxicillin and clavulanic acid(Augmentin) is very expensive and should not be used forroutine empiric therapy. Resistance among streptococciand most other dental pathogens is not attributed to betalactamase. At best, the use of this product may be aheroic option in refractory odontogenic and periodontalinfections that, on some occasions, become colonized bypenicillin-resistant Bacteroides and Prevotella speciesthat produce this enzyme.8 However, these species areanaerobic and highly susceptible to metronidazole, whichis less expensive and will be addressed later in thisreview. A more justifiable indication for amoxicillin-clavulanic acid would be a sinus graft infection in whichsubspecies of H influenzae frequently produce betalactamase.

Cephalosporins. The first generation of cephalo-sporins has a spectrum of activity that includes that ofpenicillin V for odontogenic microbes They are alsoactive against most strains of S aureus because, unlikepenicillin, they are not susceptible to beta lactamasesproduced by this species. S aureus is a commonnosocomial pathogen, and for this reason the cephalo-sporins are ordered more frequently than the penicillinsfor hospitalized patients. First-generation cephalosporinsoffer few advantages over penicillins in the managementof dental infections. As mentioned earlier, they are analternative for the penicillin-allergic patient, and certainagents have pharmacokinetic advantages that allow lessfrequent dosing. For example, the long elimination half-life of cefadroxil (Duricef) allows twice daily (BID) oraldosing, whereas cephalexin (Keflex) is administered QID.

Cefazolin (Ancef, Kefzol) is the standard first-generationagent for parenteral use.

Second- and third-generation cephalosporins exhibitan even broader spectrum and greater resistance to betalactamase. Several of the third-generation agents alsodemonstrate antipseudomonal activity. Although theseantibiotics have valuable indications in the managementof specific infectious diseases, too often they areprescribed inappropriately for infections that could bemanaged using less expensive agents. They are rarely ifever indicated for managing oral infections.

Macrolides

Macrolide antibiotics exert their antibacterial action bybinding to the 50S ribosomal subunit of susceptibleorganisms, resulting in inhibition of protein synthesis.1

Erythromycin is the prototypic macrolide and has beenprescribed historically as an alternative for patientsallergic to penicillin because it formerly had reasonableactivity against most penicillin-sensitive microbes. Thisis no longer the case, however. Macrolides have littleactivity against periodontal pathogens, and in recentyears their activity against streptococcal species hasdeclined to such a degree that most experts discouragetheir use in odontogenic infections as well. Desimone etal9 analyzed 150 cases of infective endocarditis inOlmstead County, Minnesota, that occurred from 1999through 2010. Of 22 cases attributable to viridansgroup streptococci, ~95% were sensitive to penicillinbut only ~71% to macrolides. It should be noted thatstreptococci and staphylococci that are resistant toerythromycin are also resistant to clarithromycin andazithromycin.7 Clarithromycin and azithromycin aremore active than erythromycin against Streptococcusviridans, which accounts for their mention as penicillinalternatives in current American Heart Associationguidelines for prophylaxis of infective endocarditis.10

However, it will not be surprising to see this revised infuture guidelines. In addition to growing resistanceamong odontogenic pathogens, macrolides produce ahigh incidence of nausea, and the majority of theseagents inhibit cytochrome P450 enzymes. This ac-counts for a staggering number of potential druginteractions. Furthermore, azithromycin continues tobe a concern for promoting cardiac arrhythmias insusceptible patients.11

Tetracyclines

Like the macrolides, tetracyclines are bacteriostatic butexert their antimicrobial effect by binding to the 30Ssubunit of the bacterial ribosome to inhibit protein

Figure 3. Clavulanic acid. The molecular structure of clavulanicacid resembles that of penicillin enough to compete for betalactamases that are secreted by resistant microorganisms. Thislimits the amount of enzyme available to inactivate thepenicillin.

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synthesis.1 Tetracyclines have a wide spectrum ofactivity, but microbial resistance has increased to theextent that they are seldom first-line agents for medicallytreated infections. Sinus and respiratory infectionscaused by H influenzae and pneumonococci are notableexceptions because most of these strains remainsensitive.In dental practice, tetracyclines are useful adjuncts for

managing periodontal infections. They are highly activeagainst many of the microorganisms implicated ingingival and periodontal disease and exhibit highbioavailability in the gingival sulcus. However, theirefficacy is unreliable for managing odontogenic infec-tions due to streptococcal resistance. Notably, there isless antimicrobial resistance to doxycycline and minocy-cline than to other, more conventional tetracyclines, andthese are generally preferred for periodontal infection.Like other tetracyclines, doxycycline (Vibramycin)

increases skin sensitivity to sunlight, leading to intensesunburn and generalized erythema, but offers severaladvantages. It is well absorbed in the presence of foodand has an extended elimination half-life that allows foronce-daily dosing. It is eliminated primarily in feces, andthis makes it particularly attractive for patients havinghepatic or renal compromise. Finally, even at subanti-microbial doses, doxycycline inhibits the activity ofcollagenases that contribute to the pathogenesis ofperiodontal destruction.

Metronidazole

Metronidazole is a prodrug that is converted to a toxicradical within anaerobic microbes. The radical destroysexisting DNA and other vital compounds, rendering itbactericidal against most anaerobic organisms.1 For thisreason, it is very useful for treating severe odontogenicand periodontal infections where anaerobes are able tothrive. It is not recommended as monotherapy for oralinfections because it is inactive against aerobic andfacultative streptococci. However, it may be combinedwith beta lactams when managing severe refractoryinfections. Patients should be cautioned to avoidalcoholic beverages while taking this medication becausedisulfiram-like reactions have been reported. Theseconsist of severe nausea and abdominal cramping dueto the formation of a toxic compound resemblingformaldehyde.

Clindamycin

Clindamycin binds to the 50S subunit of bacterialribosomes to suppress protein synthesis, but, unlike the

macrolides, it is bacteriocidal.1 It has reliable activityagainst both aerobic and anaerobic cocci, as well as mostspecies of Bacteroides, including Bacteroides fragilis.These pathogens are often implicated in severe orofacialinfections. Its cost and predilection for Clostridiumdifficile infection limit its routine use for dental infectionsin favor of beta lactams. However, these should not bedeterrents to using clindamycin when indicated. Indeed,C difficile infection may be a complication associatedwith amoxicillin and cephalosporins as well.

Antifungal Agents

Nystatin was formerly the most common antifungalagent used for oral candida infections but today the azolederivatives are preferred. These agents inhibit thesynthesis of ergosterol, an essential component of thefungal cell membrane. Although a variety of agents areavailable, clotrimazole (Mycelex) troches are generallypreferred based on cost and little risk for side effects anddrug interactions. Clotrimazole can be prescribed as 10-mg troches administered 5 times daily for 10–14 days.12

Fluconazole (Diflucan) is available for oral (PO) admin-istration and miconazole (Oravig) as once-daily buccaltablets, but they are very expensive. These 2 azoles alsoinhibit several families of cytochrome P450 enzymes andshould be avoided in patients taking warfarin, statins,antiretrovirals, and any drug known to prolong QTintervals.12,13

Miscellaneous Agents

The following agents have little or no indications formanaging odontogenic or periodontal infections. How-ever, some familiarity is essential for collaborativemedical management of dental patients. The mostsignificant risk for infective endocarditis is in patientshaving a prior history of this infection, especially thosewith prosthetic valves. In these cases, some cardiologistsmay prefer that an aminoglycoside such as gentamicinbe added to the prophylactic regimen. This is based onthe synergistic influence these agents have with cell wallinhibitors in killing enterococci and resistant strains of Sviridans. However, there is little scientific evidence tosupport this practice.14 For high-risk patients who areallergic to beta lactams, vancomycin may be requestedand does not require the addition of gentamicin. Theseantibiotics must be administered by intravenous infusionover 30–60 minutes preoperatively, which may requirethat treatment be arranged at an outpatient clinic if theprovider is inexperienced with this route of administra-tion.

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Aminoglycosides. Historically, the most familiarmember of this class is streptomycin, formerly the agentof choice for treating tuberculosis Gentamicin andtobramycin are used most commonly and are theprimary agents used to treat infections caused by gram-negative rods, most notably Pseudomonas species.Although most antibiotics that inhibit protein synthesisare bacteriostatic, the aminoglycosides are frequentlybactericidal. The newer generations of beta lactamantibiotics are also active against Pseudomonas species,but they are far more expensive.

The major drawback of the aminoglycosides is theirtoxicity. This includes nephrotoxicity and ototoxicity.Nephrotoxicity is fairly common, but is generallyreversible following discontinuation of the offendingdrug. Ototoxicity may include either the auditory orvestibular portions of the eighth cranial nerve. Unlikerenal cells, sensory neurons cannot regenerate, andtoxicity may be permanent. Hearing and labyrinthinefunction must be carefully monitored because initialsymptoms may be reversible provided the drug iswithdrawn quickly. Tinnitus is the earliest sign of auditorytoxicity, whereas headache and nausea generally heraldthe onset of vestibular toxicity. The various preparationsdiffer in their propensity to induce toxicity in eachdivision.

Vancomycin. Vancomycin inhibits cell wall synthesisand is active against most gram-positive cocci, includingmost species of streptococci, staphylococci, and entero-cocci1 Although enterococci were once uniformlysusceptible to vancomycin, outbreaks of infectionscaused by resistant strains are a growing problem.Scattered cases of infections caused by vancomycin-resistant enterococci are particularly sobering becausethey frequently result in mortality. Consequently, vanco-mycin is reserved for treatment of serious infectionscaused by organisms that are resistant to first-line agents,such as beta lactams, or in cases of serious allergy tothese antibiotics. This may include patients at great riskfor infective endocarditis who are allergic to betalactams, as an alternative to clindamycin.

Vancomycin can produce pseudoallergic reactions.Rapid intravenous infusion may trigger histamine re-lease, which causes a variety of symptoms, includingerythematous or urticarial reactions, flushing, tachycar-dia, and hypotension. The extreme flushing is called red-man syndrome. The most significant untoward reactionsare ototoxicity and nephrotoxicity. Auditory impairmentcan be permanent, especially with excessively highplasma concentrations. Nephrotoxicity is less common,but renal function should be monitored and appropriateplasma concentrations maintained. As might be expect-ed, toxicity is more likely when administered concur-rently with an aminoglycoside.

Fluoroquinolones. The fluoroquinolones are syn-thetic, broad-spectrum antibacterial agents that inhibitDNA gyrase, an essential enzyme that is involved in thereplication, transcription, and repair of bacterial DNA1

The introduction of quinolone derivatives is the mostsignificant recent advance in antimicrobial therapy.Ciprofloxacin (Cipro) was the first of these agentsintroduced and is regarded as the prototype. It is activeagainst most staphylococci and a variety of gram-negative microorganisms, but has poor activity againstmost streptococci and all anaerobes. This negates its usefor odontogenic and periodontal infections, whichgenerally consist of mixed aerobic and anaerobic flora(see Table 1). Newer generations of quinolones havebroader activity, but their cost generally renders theminappropriate for dental-related infections. Levofloxacin(Levaquin) has good antistreptococci action but pooranaerobic activity. Once daily dosing is attractive, but itscost is ~$25/d and its extensive antimicrobial spectrumcompletely overrules conventional principles of antibioticprescribing for odontogenic infections. Gemifloxacin(Factive) offers added anaerobic coverage but at a costof ~$50/d. At best it might be argued as an outrageouslyexpensive effort to heroically salvage a persistent peri-implant infection.

ANTIBIOTIC COMPLICATIONS

There are surprisingly few complications associated withantibiotic therapy. Other than allergy to beta lactamagents addressed previously, the principal complicationsare gastrointestinal related and potential drug interac-tions.

Antibiotic-Associated Diarrhea and Colitis

Antibiotic-associated diarrhea is not that uncommonduring a course of antibiotic therapy, but it becomes amore significant event if it is the result of C difficileinfection, a common nosocomial pathogen. This anaer-obic, spore-forming bacillus is most often contractedduring hospitalization or prolonged stays in other healthcare facilities. However, it is also found in thecommunity, and this source of infection is on the rise.Intestinal flora normally prevent colonization by Cdifficile, and it is present in only 1–4% of the generalpopulation, but .20% in those admitted to health carefacilities for a week or more.15,16 When normal flora isaltered by antibiotic therapy and the patient eitherharbors or comes into contact with C difficile, coloni-zation increases. Colonization may be enhanced by most

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antibiotics, but clindamycin, amoxicillin, second- andthird-generation cephalosporins, and the fluoroquino-lones are most often implicated.15

Colonization alone does not necessarily result in Cdifficile infection. Risk for actual infection depends onthe interaction of several additional factors, includingvirulence of the particular strain and patient-relatedfactors such as age, immune status, and the concurrentuse of acid-reduction gastrointestinal drugs, eg, protonpump inhibitors. Once C difficile infection occurs, theconsequences range from diarrhea to pseudomembra-nous colitis. Therefore, in outpatient dental practice thetypical sequence of events leading to C difficile infectionare as follows:

1. The patient is currently colonized with C difficile.(This is most likely if the patient has recently visited,has been a patient, or is a health care provider in ahospital or nursing home.)

2. Colonization is then increased by an antibioticaltering intestinal flora. (Clindamycin or amoxicillinare most likely.)

3. Patient-related factors determine risk for actualinfection and subsequent severity. (Many variablescontribute, but older age, poor immune status, anduse of acid-reduction drugs are most significant.)

The incidence of diarrhea attributed to those antibiot-ics commonly used in dentistry ranges from 2 to 10%and may be as high as 25% with amoxicillin/clavulanicacid (Augmentin).17 Clinically, the challenge is todistinguish this so-called nuisance diarrhea from thatassociated with C difficile disease. In a patient whonormally tolerates antibiotics but experiences diarrheathat is florid (�3 unformed stools per day for �2 days)and complains of abdominal pain, C difficile infectionshould be suspected. Milder symptoms in patients whohave previously experienced diarrhea with antibioticsfavor nuisance diarrhea.15,17

Mild, nuisance diarrhea may be managed usingantiperistaltics and changing the antibiotic to a narrowerspectrum if possible. However, if diarrhea is severe andC difficile infection is suspected, the following issuggested15–18:

1. Avoid antiperistaltics. Accumulation of toxin canworsen the infection.

2. Stop the current antibiotic and prescribe metronida-zole 500 mg TID 3 10–14 days.

3. If there is no improvement after 2–3 days (based onseverity), or diarrhea subsides and recurs, refer thepatient to his or her family physician, who willevaluate fluid/electrolyte status. For severe cases, thephysician may switch metronidazole to oral vanco-

mycin, which is not absorbed but provides its actionlocally within the colon. However, oral vancomycin isshockingly expensive and will be initiated only inextreme cases.

It is significant that C difficile infection has beenreported to occur as late as 6–8 weeks followingclindamycin use and has also been associated with theuse of macrolides, tetracycline, and most of the broader-spectrum beta lactam antibiotics. This complication isunheard of following abbreviated use of clindamycin forprophylaxis of infective endocarditis.

The use of probiotics to prevent or manage antibiotic-associated diarrhea remains controversial. Nevertheless,current evidence suggests they are indeed effective andshould be suggested for particularly frail patients or thosewho have experienced diarrhea with antibiotic regimensin the past.19

Antibiotic Drug Interactions

Like all drug classes, antibiotics pose a risk for druginteractions. Since the early 1980s, numerous articleshave suggested that antibiotics may reduce the efficacyof oral contraceptives (OCs). However, most of thesepublications have been either anecdotal reports orelaborate theories based on these reports. Unfortunately,many of these are found in dental literature. Anonymouscases are frequently cited in these careless reports andmention dentists who were sued for child supportfollowing an unwanted pregnancy attributed to antibiot-ic-OC interaction. None of these case reports cite legalproceedings that can be researched, and these reportsshould be viewed with suspicion. To date, rifampin (anantituberculosis agent) is the only antibiotic having aconfirmed interaction with OCs.20 Despite the equivocalstatus of this issue, the Physicians’ Desk Reference andother drug compendia continue to mention the possibil-ity of this interaction.

In a thorough review of OCs, Sondheimer21 statedthat the generally accepted rate of unwanted pregnancyamong OC users is 0.5–1% (8% among teens) and themost common reason for failure is noncompliance.Furthermore, he added that most antibiotics do notdecrease the effectiveness of the birth control pill. It isentirely within reason to suspect that a woman mightalso be taking an antibiotic during the month of OCfailure, most likely penicillin or tetracycline. To date, allhuman studies measuring the influence of antibiotics onestrogen and progestin serum concentrations have foundno interaction with antibiotics other than rifampin.1,22–24

There is simply no sound evidence to support the

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contention that antibiotics other than rifampin reducethe effectiveness of OCs.

Fortunately, the beta lactam antibiotics used tomanage dental infections are virtually free of anysignificant drug interactions. The macrolides are anentirely different matter, however. They not only have aninherent potential to lengthen cardiac repolarization andprolong QT intervals but inhibit the metabolism of manydrugs having even more potential for this cardiotoxiceffect.11,25 They also delay metabolism and elevateserum concentrations of additional drugs, leading topotential toxicity. These include warfarin, digoxin,carbamazepine, valproic acid, ergotamine, and theoph-yllines. This alarming list of potential drug interactions,combined with their declining activity against dentalpathogens, renders the routine use of macrolidesquestionable.

The potential for interactions with warfarin deservesparticular mention. Along with macrolides, metronida-zole and azole antifungals delay the metabolism ofwarfarin and must always be avoided. Other antibioticshave some potential for enhancing warfarin effects byreducing bowel flora that produce vitamin K, but thispotential is generally not a concern. Nonetheless,caution is advised when caring for older patients. Arecent publication found that exposure to several classesof antimicrobials, particularly azole antifungals, wasassociated with an increased risk of bleeding in thispopulation receiving warfarin.26

Finally, doxycycline may elevate digoxin levels andshould be avoided. It has also been found to enhancethe hypoglycemic influences of exogenously adminis-tered insulin. Diabetics receiving insulin should be

cautioned to monitor their glucose closely if doxycyclineis prescribed.

CLINICAL CONSIDERATIONS

For good reason, the selection of a particular antibiotic isbased on empirical judgment rather than culture andsensitivity data. This is because the most commonpathogens implicated in oral infections have been welldefined and the most effective antibiotics con-firmed.7,8,27

The effectiveness of a particular antibiotic for manag-ing specific infections is predicated on 3 variables: (a) theantibiotic’s minimum inhibitory concentration (MIC)-90for the pathogen, (b) its peak serum level, and (c) itselimination half-life.

a. The MIC-90 represents the serum concentrationrequired to inhibit or destroy 90% of the species fora selected class of microorganisms. It is important toconsider that an antibiotic may exhibit activity invitro, but it is of little use if this concentration cannotbe achieved in the tissue infected.

b. Following PO administration, serum concentrationmust exceed the MIC-90.

c. An antibiotic is ineffective if its elimination patterndoes not sustain an acceptable serum concentrationfor a reasonable period of time. Concentration dropsby 50% each half-life.

Data for the application of these principles toantibiotics used in dental practice are presented in Table1. Precise data will vary depending on the reference text

Table 1. Antibiotic Susceptibility Data for Selected Antibiotics*7

Data Penicillin V Amoxicillin Cephalexin Clindamycin Ciprofloxacin

PO dose (mg) 500 500 250 300 500Peak serum level (lg/mL) 4 7.5 5.8 3.6 2.4T1/2 (h) 0.5–0.75 1.4–2.0 0.5–1.2 2.4 4MIC-90 (lg/mL)Streptococcus viridans 0.01 0.05 0.12 0.06–256 4Peptostreptococcus 0.5 0.2 † 0.1–.100 2–6.25Prevotella 0.5 0.5 † 0.03–.128 16–.64Haemophilus influenzae‡ 0.8 0.5 16 0.4–50 0.015–0.06Bacteroides fragilis§ .32 .32 .32 0.03–.128 4–64

* MIC indicates minimum inhibitory concentration; PO, oral; T1/2, elimination half-life. The MIC-90 of penicillin V for S viridansis 0.01 lg/mL. Its peak serum concentration following oral administration of 500 mg is 4 lg/mL and its serum half-life is 0.5–0.75hours. Following its administration and allowing 1 hour for peak concentration to be achieved, serum concentrations of penicillin Vwill remain above the MIC-90 for ~6–7 half-lives. For this reason, penicillin V is considered highly effective for managing mostodontogenic infections. Notice that this would not be the case for managing severe dental infections attributed to B fragilis, butclindamycin is effective. Also note the basis for amoxicillin being prescribed 3 times daily rather than 4 times daily for penicillin V andmoreover that fluoroquinolones such as ciprofloxacin are ineffective for dental pathogens.

† No precise data on these species, but activity is similar to that of penicillins.‡ Implicated in primary sinus infections.§ Often present in severe cellulitis due to odontogenic infections.

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consulted, but will be reasonably similar to that derivedfrom Mandell et al.7

Treatment of Existing Infection

There are 3 essential principles to follow whenmanaging odontogenic and periodontal infections:

1. The source of the infection should be removed.2. If the infection is too severe for the patient’s natural

immune system to manage, antibiotic therapy isindicated.

3. Select an antibiotic with the narrowest spectrum thatincludes the most likely pathogens.

A stepped approach can be used to empirically selectantibiotics for managing existing dental infections.Treatment should commence with either a penicillin, acephalosporin, or, rarely, a macrolide. Antibiotic therapydoes not obviate the need for surgical drainage when thisis possible. If the condition deteriorates or fails toimprove over the subsequent 2–3 days, either addmetronidazole to the current regimen or switch theregimen to clindamycin. This principle is illustrated inFigure 4. If this second step fails, more aggressivesurgical drainage is indicated and culture/sensitivity datamay be used to guide further antibiotic selection. Ifcellulitis evolves, a dentist is wise to at least consult, andpreferably to refer the patient to, an oral and maxillo-facial surgeon for definitive management.The duration of antibiotic coverage is empiric; there

are no precise standards for duration of coverage. Mostdental-related infections will resolve within 5–7 days and,provided the patient’s signs and symptoms resolve, thereis little reason to provide longer coverage. The idea thatcoverage should extend for several days followingcomplete remission to prevent recurrence is a miscon-ception. Dental infections do not rebound provided thesource of infection has been corrected.

The dose of the antibiotic selected should achievelevels in the infected tissues that exceed the MIC-90 forthe targeted microorganisms. The actual concentrationsattained in various tissues are not always as high as thosein serum, so it is prudent to strive for persistent serumlevels at least 2–5 times the MIC-90. For severeinfections it may be wise to double the first dose (loadingdose) to establish a high initial concentration to promotedistribution into the infected tissues. Antibiotic dosagesfor managing dental infections are summarized inTable 2.

The elimination half-life of the antibiotic will predictthe rate of decline in the serum level, and thisconsideration is used by the drug manufacturer inestablishing the recommended dosing interval. Providedthe patient is compliant with the published dosingschedule, serum levels will remain above the MIC-90.Compliance is most critical for the beta lactam antibioticsbecause of their mechanism of action. These drugsinterfere with cell wall synthesis and must be present inadequate concentration at any time the microbeattempts cell division. Other classes of antibiotics, suchas macrolides, clindamycin, tetracycline, and metronida-zole, are somewhat forgiving because they exhibit so-called postantibiotic effects. This property defines theantibiotic’s ability to continue its influence on microor-ganisms for varying periods of time after the serum levelhas declined below the MIC-90. There are manymechanisms proposed for the postantibiotic effects ofvarious antibiotics, including an ability to reside withinthe cytoplasm of the microbes, suppressing theirbiochemical pathways (metronidazole), or residing withinmacrophages, where microbes become exposed duringphagocytosis (macrolides).

Routine Surgical Prophylaxis

The concept of surgical prophylaxis is often misunder-stood. Its premise is that the surgical site is currently not

Figure 4. Step approach to empiric antibiotic therapy.

Table 2. Antibiotics and Dosages for Dental Infections*

Preparation Conventional Dosing Schedule1

Penicillin V 500 mg QIDAmoxicillin 500 mg TIDCephalexin (Keflex) 500 mg QIDCefadroxil (Duricef) 500 mg BIDClindamycin (Cleocin) 300 mg TID or QIDMetronidazole (Flagyl) 500 mg TID or QIDDoxycycline (Vibramycin) 100 mg QID or BID

* QID indicates 4 times daily; TID, 3 times daily; and BID,twice daily.

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infected, but may become contaminated during surgery.This condition is not present when removing abscessedor periodontally compromised teeth; infection is current-ly present. Prescribing antibiotics during or followingthese cases is not prophylaxis. It represents therapeuticuse of antibiotics to manage infected tissues and isfrequently unnecessary after the offending culprits aresurgically removed.

Antibiotic prophylaxis may be indicated when openingflaps to remove impactions or for dental implants andgrafting procedures. In these cases, the surgical site is notinfected at the start of surgery, and it may be appropriateto administer an antibiotic preoperatively to decrease thelikelihood of introducing an infection. When usingantibiotic prophylaxis, an adequate serum concentrationshould be established no earlier than 2 hours before asurgical incision is made, and should not be repeatedunless the procedure is prolonged (.3 hours). In thiscase a dose may be repeated at intervals correspondingto 1–2 elimination half-lives for the drug used.28

Prolonged coverage will encourage growth of resistantorganisms, and this may be especially relevant forsuccess with implant placements. There is absolutelyno rationale to commence antibiotic therapy followingsurgery, deeming it prophylaxis.

A reasonable prophylaxis regimen for dental surgerywould be the amoxicillin regimen suggested for preven-tion of infective endocarditis. For those preferring anintravenous regimen, cefazolin (Ancef, Kefzol) is attrac-tive because it is inexpensive and provides effectivecoverage for 8 hours, similar to amoxicillin. This can befollowed with an oral cephalosporin or amoxicillin toextend the coverage, but additional doses are generallynot recommended, certainly for no more than 24hours.28 Suggested regimens for routine surgical pro-phylaxis are summarized in Table 3.

Medical Prophylaxis

Unlike routine surgical prophylaxis, medical indicationsfor antibiotic prophylaxis are predicated neither on thepresence nor on the absence of current infection. Thebasis for these indications is either a great potential forpostoperative infection of the surgical site or distant-siteinfections attributable to surgically induced bacteremia.

Immunocompromised patients heal poorly and are atgreater risk for developing infections. Examples ofconditions that may be associated with poor immunestatus include the following, and dentists often provide acourse of antibiotics when performing dental surgery forthese patients:

� Poorly controlled diabetes.� Systemic lupus erythematosus.� End-stage renal disease undergoing dialysis.� Evidence of significant malnutrition or alcoholism.� Symptomatic human immunodeficiency virus–positive

patients.� Patients receiving immunosuppressant drugs or radi-

ation to head and neck.

Although some authors suggest this practice, there areno published guidelines. Lockhart et al29 have publishedan impressive review of scientific literature and found noscientific basis for this practice. Nevertheless, the dentistmay empirically justify coverage in some cases. Ifprophylaxis is elected, however, it is doubtful thatpreoperative doses provide any particular benefit;coverage may commence postoperatively and continuefor 5–7 days. The only exception is the dialysis patientwith an arteriovenous shunt. For these patients, preop-erative prophylaxis may be indicated, but only ifperforming incision and drainage of an abscess.29

Other medical indications for antibiotic prophylaxisare predicated on a potential for distant-site infections asa consequences of bacteremia, but even these arefrequently challenged. Surgical and invasive diagnosticprocedures may certainly introduce bacteria into thebloodstream (bacteremia), but this is of little consequenceunless a patient has some distant site that is susceptibleto microbial colonization. Unfortunately, there is littlescience to establish which sites or devices are actuallysusceptible to colonization.

Table 3. Suggested Regimens for Routine SurgicalProphylaxis*

Preparation Dosing Schedule†

Penicillin V 2 g PO/1 h preop; 6 1 g q 6 h 3 1Amoxicillin 2 g PO/1 h preop; 6 1 g q 6 h 3 1Cephalexin 2 g PO/1 h preop; 6 1 g q 6 h 3 1Clindamycin 600 mg PO/1 h preop; 6 300 mg q

6 h 3 1Intravenous regimensCefazolin 1 g IV 30 min preop; 6 postop PO

as aboveDilute powder in 5 mL and administerover 3–5 min

Clindamycin 600 mg IV 30 min preop; 6 postopPO as above

Dilute in 50 mL and administer over20 min

* Dosages derived from Drug Facts and Comparisons inClin-Eguide.1 PO indicates oral; preop, preoperatively; IV,intravenous; and postop, postoperatively.

† Postoperative dose is rarely indicated.

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The American Heart Association recommends thatpatients at risk for infective endocarditis receive prophy-lactic antibiotics prior to dental and other surgicalprocedures. The antibiotics recommended are those thatare most active against the specific microbes likely to beintroduced during the specific procedure. The mostrecent guidelines for prevention of infective endocarditisin patients undergoing dental procedures were publishedin 2007 and are summarized in Table 4.10 It is significantthat former concerns regarding valvular disease, eg,murmurs, are no longer recommended for prophylaxis.Although penicillins are generally preferred, macrolides,clindamycin, and cephalosporins are acceptable alterna-tives for patients having a penicillin allergy. As men-tioned previously, resistance to macrolides is increasingand any recommendation for their use may be modifiedin future guidelines.9

In some cases, a patient may present for treatmenthaving not premedicated. The following is a direct quotefrom the current American Heart Association guidelines;simply stated, administer the antibiotic regimen andcomplete the treatment!

An antibiotic for prophylaxis should be administeredin a single dose before the procedure. If the dosage of

antibiotic is inadvertently not administered before theprocedure, the dosage may be administered up to 2hours after the procedure. However, administration ofthe dosage after the procedure should be consideredonly when the patient did not receive the pre-procedure dose.10

The risk for hematogenous seeding and infection oftotal joint prostheses are more controversial. Littleinformation has been published on this matter, butBerbari et al30 have published the most significantresearch and found no increased risk. The AmericanDental Association and American Academy of Ortho-paedic Surgeons published updated guidelines in 2012that suggest discontinuing routine antibiotic prophylaxisfor all patients having joint replacements.31 A summaryof these rather vague guidelines is as follows:

1. The practitioner might consider discontinuing thepractice of routinely prescribing prophylactic antibi-otics for patients with hip and knee prosthetic jointimplants undergoing dental procedures.

2. We are unable to recommend for or against the useof topical oral antimicrobials in patients with pros-

Table 4. Summary of Current Guidelines for Prevention of Infective Endocarditis10

Medical Indications Dental Procedures

1. Prosthetic heart valve2. Previous bacterial endocarditis

All procedures that manipulate gingival or periapical tissues,or those that perforate oral mucosa EXCEPT:

3. Cardiac transplantation that develops valve defects4. Specified CHD:� Unrepaired cyanotic CHD (eg, tetralogy and VSD)� All repairs for 6 mo after placement� All repairs with residual defects

� Anesthetic injections through noninfected tissues� Placement of removable prosthetics� Any orthodontic appliance including brackets� Shedding of deciduous teeth or trauma to oral mucosa

Drug Adult Dose (Child Dose)Standard regimen:Amoxicillin PO: 2 g; 1 h preop (50 mg/kg)Ampicillin IM/IV: 2 g; 1/2 h preop (50 mg/kg)

Penicillin allergy:Clindamycin PO: 600 mg; 1 h preop (20 mg/kg)

IV: 600 mg; 1/2 h preop (20 mg/kg)Clarithromycin or azithromycin PO: 500 mg; 1 h preop (15 mg/kg)Cephalexin† PO: 2 g; 1 h preop (50 mg/kg)Cefazolin† IM/IV: 1 g; 1/2 h preop (50 mg/kg)

Pediatric Doses‡Child Weight Proportion of Adult Dose

,15 kg 1/415–30 kg 1/230–40 kg 3/4.40 kg Adult dose

* CHD indicates congenital heart disease; VSD, ventricular septal defect; PO, oral; preop, preoperatively; IM, intramuscular; andIV, intravenous.

† Cephalosporins can be used as an alternative to amoxicillin, provided the allergic reaction was limited to rash and/or itching.History of urticaria (hives) or anaphylactoid symptoms is a contraindication for using any beta lactam derivative.

‡ Approximations by author based on 50 mg/kg for beta lactams and 20 mg/kg for clindamycin.

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thetic joint implants or other orthopaedic implantsundergoing dental procedures.

3. In the absence of reliable evidence linking poor oralhealth to prosthetic joint infection, it is the opinion ofthe work group that patients with prosthetic jointimplants or other orthopaedic implants maintainappropriate oral hygiene.

Regardless of continued controversy, the dentist maystill encounter a patient whose orthopedist requestsantibiotic coverage. In this case it is my personal practiceto honor the request and cover the patient usingregimens identical to those suggested for prophylaxisof infective endocarditis. Unless a patient volunteers hisor her orthopedist’s request for antibiotic prophylaxis, Ido not broach the subject.

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2. Campagna JD, Bond MC, Schabelman E, Hayes BD.The use of cephalosporins in penicillin-allergic patients: aliterature review. J Emerg Med. 2012;42:612–620.

3. Solensky R. Allergy to beta-lactam antibiotics. J AllergyClin Immunol. 2012;130:1442.

4. Abramowicz M, ed. Cephalosporins for patients withpenicillin allergy. Med Lett Drugs Ther. 2012;54:101.

5. Stern RS. Clinical practice. Exanthematous drug erup-tions. N Engl J Med. 2012;366:2492–2501.

6. Solensky R, Kahn DA. Drug allergy: an updated practiceparameter. Ann Allergy Asthma Immunol. 2010;105:259–273.

7. Mandell GL, Bennett JE, Dolin R. Mandell, Douglas,and Bennett’s Principles and Practice of Infectious Diseases.7th ed. Philadelphia, Pa: Churchill Livingston (Elsevier), 2009.

8. Kuriyama T, Karasawa T, Nakagawa K, Yamamoto E,Nakamura S. Incidence of beta-lactamase production andantimicrobial susceptibility of anaerobic gram-negative rodsisolated from pus specimens of orofacial odontogenic infec-tions. Oral Microbiol Immunol. 2001;16:10–15.

9. Desimone DC, Tleyjeh IM, Correa de Sa DD, et al.Incidence of infective endocarditis caused by viridans groupstreptococci before and after publication of the 2007 AmericanHeart Association’s endocarditis prevention guidelines. Circu-lation. 2012;126:60–64.10. Wilson W, Taubert KA, Gewitz M, et al. Prevention of

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29. Lockhart PB, Loven B, Brennan MT, Fox PC. Theevidence base for the efficacy of antibiotic prophylaxis in dentalpractice. J Am Dent Assoc. 2007;138:458–474.30. Berbari EF, Osmon DR, Carr A, et al. Dental procedures

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CONTINUING EDUCATION QUESTIONS

1. Which of the following are accurate statementsregarding cross-allergenicity among penicillins andcephalosporins?

(1) It is related to the fact they share a beta lactamring in their structure. (2) Cross-reactions areunlikely with histories of only pruritus or rash. (3)Cephalosporins should be avoided if a patient hasexperienced airway swelling following use of apenicillin.

A. 1 and 2B. 1 and 3C. 2 and 3D. 1, 2, and 3

2. Which of the following has the least activity againstodontogenic pathogens?

A. ciprofloxacinB. clindamycinC. cephalexinD. erythromycin

3. The principal reason beta lactam antibiotics contain-ing clavulanic acid or sulbactam are rarely indicatedwhen managing dental infections is because

A. of their extreme cost.B. they produce a high incidence of nausea and

diarrhea.C. they produce numerous drug interactions.D. resistance among dental pathogens is rarely

due to beta lactamase.

4. All of the following antimicrobial agents should beavoided in patients who are anticoagulated withwarfarin EXCEPT:

A. erythromycinB. clindamycinC. fluconazoleD. metronidazole

Anesth Prog 60:111–123 2013 Becker 123