Chemotherapeutic agents used in periodontics

Microbial plaque is the primary etiology of periodontal diseases and its removal with mechanical therapy (such as scaling, root planing, and power instrumentation) is considered as a gold standard to achieve periodontal health. In addition to the mechanical therapy, many chemotherapeutic agents, including antimicrobials and host modulation agents have been used to achieve better results. A chemotherapeutic agent is a general term for a chemical substance that provides a clinical benefit. This term does not signify the method by which the agent provides clinical benefit. It may be by reducing or eliminating infective agents such as bacteria, fungi or viruses or by modulation of the host response, reducing tissue damage caused by this response.

Rationale of using chemotherapeutic agents in periodontal diseases

The primary rationale of using chemotherapeutic agents is to eliminate, reduce or alter the effects of microorganisms in the oral cavity and elevated levels of pro-inflammatory mediators. Although, mechanical debridement removes bacterial plaque and debris which is responsible for periodontal breakdown, but some individuals continue to experience periodontal attachment loss even after adequate mechanical debridement. This continued periodontal breakdown has been explained due to the ability of major periodontal pathogens to invade the periodontal soft tissues. It has been shown that various periodontal pathogens such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Fusobacterium-nucleatum, Treponema denticola, Bacteroides 1, 2 can invade the periodontal soft tissues. Also, the bacterial biofilm may be difficult to remove with mechanical debridement from difficult to reach areas, such as furcation areas. The virulence factors secreted by various bacterial species have been shown to cause direct or indirect bone loss. Thus, elimination or reduction of microbial load is essential to achieve periodontal health.

Another important rationale of using chemotherapeutic agents is poor host defense 3. Patients with acute periodontal diseases such as acute necrotizing ulcerative gingivitis and necrotizing ulcerative periodontitis are candidates which may get benefited from anti-microbial therapy. The success of antimicrobial therapy depends on the susceptibility of bacteria to the antimicrobial agent.

Desired properties of an anti-microbial agent:

  1. Effectiveness against specific pathogens
  2. Non-toxic to oral tissues and minimal side effects
  3. Does not cause overgrowth of other organisms
  4. Does not contribute to the development of bacterial resistance
  5. Substantiveness: resists dilution

Classification of anti-microbial agents

The anti-microbial agents can be classified on the basis of their mechanism of action and their spectrum of antimicrobial activity.

Based on their mechanism of action:

Agents that inhibit synthesis of bacterial cell walls

  • Penicillins
  • Cephalosporins
  • Monobactams

Agents that interfere with the cell membrane of the microorganism, affecting permeability

  • Some antifungal agents.

Agents that inhibit protein synthesis by affecting the function of the 30S or 50S ribosomal subunits

  • Tetracyclines
  • Macrolides
  • Clindamycin

Agents that block important metabolic steps of the microorganisms

  • Sulfonamides
  • Trimethoprim

Agents that interfere with nucleic acid synthesis

  • Metronidazole
  • Quinolones

Based on their spectrum of activity:

  • Broad spectrum (active against both Gram-positive and Gram-negative organisms. Examples include: tetracyclines, phenicols, fluoroquinolones, “third-generation” and “fourth-generation” cephalosporins).
  • Narrow spectrum (have limited activity and are primarily only useful against particular species of microorganisms. Example include: Aminoglycosides and sulfonamides, which are effective only against aerobic organisms and nitroimidazoles which are generally effective only against anaerobes.)

Classification of chemothrapeutic agents

Classification of chemotherapeutic agents

Antibacterial agents

The most commonly used chemotherapeutic agents in the treatment of periodontal diseases are anti-bacterial agents. Before we discuss these agents, it is important to know the difference between antibiotics and anti-microbial agents. An antibiotic is……………

123

Routes of administration:

These agents can be administered systemically or locally (local drug delivery). The most commonly used route of drug administration is the systemic route. The bacteriostatic or bactericidal concentration of anti-microbial agents can be safely achieved by systemic administration of these drugs. The drug can reach the periodontal tissue and pocket via serum and act on bacteria in periodontal tissue and the base of the pocket. Certain drugs like tetracycline, when administered systemically achieves more concentration in gingival crevicular fluid (GCF) as compared to serum 4. The drug can then bind to the tooth surface, from which it is released in active form 5. However, systemic administration is associated with side-effects. Further, the bacteria in the biofilm are much more resistant to these antimicrobials because of the protection provided by the protective layer covering the biofilm. The administration of systemic antibiotic therapy should be considered for a particular patient based on its potential benefits and side effects. As already stated, patients with limited response to an adequate mechanical therapy are indicated for systemic antibiotic therapy.

On the other hand, local drug delivery provides a high concentration of drug when placed in the periodontal pocket. The drug can be placed in the periodontal pocket where it releases the drug in an active form for a particular duration of time. However, there are both systemic and local drug delivery has their own advantages,

Advantages of systemic drug delivery:

  1. Antimicrobial activity can be achieved at multiple sites and also at the reservoir sites such as tongue, tonsils and buccal mucosa.
  2. The organisms residing at the base of the pocket and in periodontal tissue can be reached.
  3. A shorter time of administration.
  4. A large number of antimicrobials and their combinations are available for systemic use.
  5. Low cost.

  Advantages of local drug delivery:

  1. It provides a highly concentrated form of the drug without any systemic side effects.
  2. Patient compliance is improved.
  3. Because of the highly concentrated form of drug, chances of development of resistance are minimal.

Criteria for prescribing antibiotic therapy

There are many factors which should be considered before an antibiotic is prescribed to a patient. These criteria include:

Whom to treat?

The clinical condition of the patient should dictate the need for antibiotic therapy. Patients who do not respond appropriately to standard periodontal treatment such as patients with aggressive periodontitis, patients with refractory periodontitis and acute periodontal lesions such as necrotizing ulcerative gingivitis or periodontitis. In general, patients who demonstrate multiple sites with periodontal pockets ≥ 5 mm and in whom a periodontal infection can be diagnosed are the patients indicated for antibiotic therapy. Most of the clinicians prefer to give systemic antibiotic therapy to a patient scheduled for periodontal surgery.

Microbial culturing and culture sensitivity:

The anti-microbial should be ideally selected on the basis of culturing of the plaque sample obtained from periodontal pocket and its culture sensitivity test. The plaque samples may be obtained from recently active pockets or the pool of plaque samples obtained from deep pockets in different parts of the oral cavity. One advantage of the pooled plaque sample is that the range of periodontal pathogens present in plaque samples against which antimicrobial therapy is required can be determined 6. The plaque sample should be collected before instrumentation. The supragingival plaque is removed and the absorbent paper point is introduced in the deepest pocket or pockets to engage loosely attached plaque. The paper point is then put in a transfer medium and is sent to the laboratory for culture. The laboratory, then cultures the sample and informs the dentist regarding the bacterial species present in the sample and also the most suitable antibiotic regimen.

Starting the antibiotic therapy:

As already stated, the physical disruption of biofilm is essential to achieve maximum benefit from antibiotic therapy because bacteria in a well-organized biofilm are 500-1000 times more resistant to antibiotics as compared to planktonic bacteria 7. Slots et al. (1999) 8 have reported that…………………….

123

Periobasics: A textbook of Periodontics and Implantology
For India Users:
Buy Now
For International Users:

Consultation with the patient:

The patient should be explained in detail the need for antibiotic therapy and its potential benefits. The patient should also be explained the side-effects that are related to the use of a particular antibiotic.

Choice of systemic administration of antibacterial agents:

The choice of an antibiotic ideally depends on the microbial analysis and antibiotic sensitivity test. However, most of the times the choice of antibiotic is made on the basis of clinical signs. The most commonly used antibiotics in periodontal treatment include β-lactams (amoxicillin with or without clavulanic acid), tetracyclines (tetracycline, doxycycline, minocycline), metronidazole and clindamycin. The clinician should be well versed with the pharmacokinetics, pharmacodynamics, and spectrum of action of antibiotics and their rational use in clinical conditions. There are various factors which should be considered while choosing an antibiotic and its dose for a particular patient. These include,

Choosing anti-bacterial agent for empirical therapy:

Most of the times the antibiotics are prescribed based on the clinical presentation of the disease. So, choosing of antibiotic should be evidence based and according to the patient’s need.

Spectrum of chosen drug:

The spectrum of the drug should include the targeted organism/organisms. In empirical therapy usually, broad-spectrum antibiotics are given so that all suspected organisms are covered, whereas, in rational therapy, a narrow spectrum drug should be given which targets only the identified organism/organisms.

Age of the patient:

The pharmacokinetics of drugs is to a great extent depends on the age of the patient. In old age, the dose of the drug is usually reduced due to its slow clearance from the body. Use of particular antibiotics may not be suitable for a particular age group. For example, tetracyclines accumulate in the developing teeth and bone, so their use in young children is not recommended.

Status of renal and hepatic function:

The drugs are metabolized mostly in the liver or kidneys. So, the hepatic and renal function have to be considered while prescribing any drug to a patient.

Patients with compromised host response:

In patients who are systemically compromised should be considered for aggressive antibiotic therapy. In an immunocompetent individual, a bacteriostatic antibiotic may be sufficient to control the growth and multiplication of microorganisms, but in an immunocompromised individual, appropriate bactericidal dose of antibiotic is necessary to control the growth and multiplication of microorganisms.

Pregnancy:

All efforts should be done to avoid antibiotic therapy during pregnancy because these may have adverse effects on the developing fetus. However, when required antibiotic should be prescribed following the FDA classification of drugs during pregnancy (See chapter 30 “Periodontal treatment of female patients”).

Patient already taking medications:

Many drugs may have an adverse reaction with each other when given together. Some drugs may potentiate the effectiveness of other drugs or may reduce it. So, a complete medical history of the patient is essential before any medicine is prescribed.

Drug allergy:

Allergic reaction to a specific drug may be life threatening. So, any allergic reaction to a drug should be carefully recorded while taking the case history.

Principles of anti-bacterial drug dosing

The dose of anti-bacterial agent is decided on the basis of its minimum inhibitory concentration (MIC) and gingival fluid concentration (CGCF). MIC90 or minimum inhibitory concentration 90% is the concentration of drug that will inhibit the growth of 90% of the bacterial strains of a species that are tested in vitro. The effectiveness of the drug in periodontal pocket is determined by the relationship between CGCF and MIC90.

100 (CGCF/MIC90) = antimicrobial activity expressed as a percentage for each antibiotic and each organism.

While deciding the dosage of an antibacterial agent, following points should be considered,

  • Some anti-bacterial agents require a high concentration of the drug (above MIC) in plasma and tissues for effective bacterial killing. These agents include aminoglycosides, metronidazole, and quinolones. On the other hand, other agents require a prolonged exposure to the bacteria to be effective. These agents include beta-lactams.
  • The dosing interval depends on.

Problems associated with the use of anti-microbial therapy in periodontal diseases

There are some basic problems associated with the use of various anti-microbial agents in periodontal diseases. The first and the foremost problem is that periodontal diseases are multi-factorial disease. Although, bacterial etiology is the primary etiology of most of the periodontal diseases, but many systemic, environmental and genetic factors are also associated with periodontal disease progression. The second problem is that multiple microorganisms are associated with periodontal diseases consisting of both Gram-positive and Gram-negative bacteria. Most of these bacteria are a component of both normal as well as pathogenic flora. Thirdly, the clinical diagnosis is primarily made on the basis of clinical findings and not on the basis of molecular findings.

The anti-bacterial agents used have their specific spectrum of activity against Gram-positive or Gram-negative bacteria. Most of the times empirical therapy is used based on the clinical findings and most probable microorganisms involved in a particular periodontal condition.

Commonly used anti-bacterial agents in periodontics

Penicillins:

Penicillin was discovered by Sir Alexander Fleming in 1928 which started a new era of infection control in human history. Penicillins exert their antibacterial action via inhibiting the bacterial cell wall synthesis, thus resulting in cell death. Structurally all penicillins are composed of a β-lactam ring, a thiazolidine ring, and an acyl side chain (Figure 47.1). Various different penicillins have been derived by substituting the acyl side chain in its basic structure. These include benzylpenicillin, phenoxymethylpenicillin, and more broad-spectrum drugs, such as amoxicillin and ampicillin. The variation in the acyl side chain in different penicillins results in significant variations in their properties in terms of improvement in stability to gastric acid, improvement in absorption and higher serum concentrations, and activity against Gram-negative as well as Gram-positive bacteria.

Figure 47.1 Structure of Penicillins

Structure of Penicillins

Pharmacokinetics:

Penicillins can be administered both orally and parenterally, but benzylpenicillin can only be given parenterally because it is not stable in acidic medium in the stomach. For oral penicillins (phenoxymethylpenicillin, amoxicillin, and ampicillin), the usual dose is 250 mg every 8 hours. The dose can be increased in severe infections, such as in severe dental infections 3 g loading dose of amoxicillin followed by 8 hourly administration has been recommended 10. Absorption of penicillins takes place in the upper gastrointestinal tract. The absorption rate may get reduced due to the presence of food but amoxicillin is one of the most readily absorbed penicillin. Penicillins get easily distributed in the body, but do not cross the blood-brain barrier because of their lipid insolubility. These get partially bound (46-58%) to proteins and are eliminated from the body via filtration from the kidneys.

Antibacterial spectrum:

Penicillin group of drugs consists of many derivatives of penicillin with varying range of the antibacterial spectrum. Some of them are effective against many Gram-positive and Gram-negative bacteria while some are effective against only limited bacterial species (Table 47.1).

Table 47.1 Antibacterial spectrum of various penicillins

Type of anti-microbial agent
Examle
Narrow spectrum penicillinsPenicillin G
Penicillin V
Broad spectrum penicillins (aminopenicillins)Amoxicillin
Ampicillin
Bacampicillin
Penicillinase-resistant penicillinsCloxacillin
Nafcillin
Methicillin
Dicloxacillin
Oxacillin
Extended spectrum penicillinsCarbenicillin
Mezlocillin
Piperacillin
Ticacillin
β-lactamase inhibitorsClavulanic acid
Sulbactam
Tazobactam

Mechanism of resistance:

There are three mechanisms by which bacteria offer resistance to penicillins: decreased permeability of the cell wall to the antibiotic, alteration in penicillin binding proteins and by producing β-lactamases.

Decreased permeability of bacterial cell wall: The structure of the cell wall of Gram-positive and Gram-negative bacteria is different. Antibiotics can easily diffuse through the cell wall of Gram-positive bacteria due to its simple structure made up of peptidoglycan polymer. On the other hand, the bacterial cell wall in Gram-negative bacteria is complex, made up of lipopolysaccharide that acts as a barrier to hydrophobic compounds. There are some aqueous channels in the outer membrane formed by proteins called porins, which allow passage of small hydrophilic antibiotic molecules. However, Specific gene mutations coding for the porin proteins impair the entry of antibiotic molecules into the cell, thus resulting in increased resistance to antibiotics 11.

Alteration in penicillin-binding proteins: To exert their bactericidal action, penicillins bind to specific proteins in the bacteria named penicillin binding proteins. Alteration in these proteins may result in the increased resistance of bacteria to antibiotic. This type of resistance has been observed in methicillin-resistant staphylococci 12 and in penicillin-resistant Gonococcal strains 13.

Production of β-lactamases: This is the most important mechanism of bacterial resistance to penicillins and cephalosporins. The resistance is offered by the production of β-lactamase enzyme which causes hydrolysis of the β-lactam ring, resulting in inactivation of the antibiotic. β-lactamases are produced in large quantity by Gram-positive bacteria as compared to Gram-negative bacteria where these enzymes are found in relatively small amounts primarily located in the periplasmic space. The presence of these enzymes in the periplasmic space offers maximum resistance to bacteria because, in this strategic location, even a small amount of enzyme is sufficient to inactivate antibiotic molecules. Inhibitors of β-lactamase such as clavulanic acid can be combined with penicillins to prevent hydrolysis of the β-lactam ring in these antibiotics.

Clinical uses in periodontal diseases:

It has been shown that amoxicillin, ampicillin, and augmentin are effective in refractory periodontitis either used alone 14 or in combination with metronidazole 15. However, most of the periodontal pathogens are Gram-negative and are not sensitive to penicillins so mostly penicillins are used in combination with other drugs which have Gram-negative spectrum. Furthermore, penicillin-resistant organisms do not respond to various penicillins so clavulanic acid is added which neutralizes β-lactamases produced by these organisms.

Adverse effects:

The major side effect associated with the use of penicillins is anaphylaxis and the development of resistance. The anaphylactic reaction is a medical emergency and should be managed appropriately (discussed in detail in “Treatment of medically compromised patient”). Other side effects include diarrhea and skin rashes which are more common with ampicillin. In susceptible patients, cross hypersensitivity exists for all penicillins. So, once identified, no derivative of penicillin group should be given to a hypersensitive patient.

Cephalosporins:

Cephalosporins are β-lactam antibiotics that differ from the penicillins in that the B ring is a 6- membered dihydrothiazine ring (Figure 47.2). The mechanism of action of cephalosporins is similar to that of penicillin. These bind to the penicillin-binding proteins in the bacterial cell and inhibit cell wall synthesis. In general, cephalosporins are less susceptible to β-lactamases as compared to penicillins. Presently, there are many cephalosporins available which can be classified based on their antibacterial properties and when they were introduced (Table 47.2).

Figure 47.3  General structure  of cephalosporins showing âlactam  ring,  acyl  side  chain  and  dihydrothiazine ring

Structure  of cephalosporins

Various properties of cephalosporins such as pharmacokinetics, plasma half-life, metabolism and their excretion vary from drug to drug in this group. Because there are a large number of drugs in this group, readers are advised to go through pharmacology books for their detailed description. The commonly used cephalosporins, cefaclor and cephalexin have good oral bioavailability and achieve high concentrations in GCF. Cephalexin effectively inhibits the growth of Gram-negative obligate anaerobes but fails to inhibit the Gram-negative facultative anaerobes 16. More research is required on newer cephalosporins, which are more effective against Gram-negative bacteria implicated in periodontal disease progression.

Table 47.2 The generations of cephalosporins 

Generation
Drugs
Antibacterial spectrum
First generationCefazolin
Cefadroxyl
Cephalexin monohydrate
Cefradine
Active against Gram-positive bacteria;
Moderately active against Gram-negative bacteria,
Streptococci (except penicillin-resistant strains)
Second generationCefuroxime
Cefuroxime axetil
Cefprozil
Cefmatazole
Loracarbef
Increased activity against Gram-negative, but much less active than third generation cephalosporins.
Third generationCefotaxime
Ceftriaxone
Cefdinir
Cefditoren pivoxil
Ceftizoxime
Ceftibuten
Cefpodoxime proxetil
Cefoperazone
Ceftazidime
Less active than the first generation against Gram-positive bacteria, but more active against Enterobacteriaceae including -lactamase producing bacteria
Fourth generationCefepimeExtended spectrum of activity than the third generation and have increased stability against hydrolysis by - lactamase

Tetracyclines:

Tetracyclines belong to a group of broad-spectrum antibiotics which also includes other antibiotics, namely doxycycline, lymecycline, minocycline, demeclocycline, and oxytetracycline. These are active against both Gram-positive and Gram-negative bacteria. These drugs exert their bacteriostatic action via binding to the bacterial 30S ribosomal subunit and inhibiting protein synthesis. However, when used in a high concentration, such as in local drug delivery, these exert a bactericidal action by their ability to cause alterations in the cytoplasmic membrane. The alterations in the cytoplasmic membrane result in the leakage of the cellular content and finally resulting in cell death. The chemical formula of tetracycline is C22H24N2O8 (Figure 47.3 a) and that of doxycycline is C22H24N2O8 (Figure 47.3 b).

Figure 47.4 Chemical structure of tetracycline (A) and doxycycline (B)

Chemical structure of tetracyclines

Pharmacokinetics:

The most common route of administration of tetracyclines is oral. These are rapidly absorbed from the intestinal tract. Tetracycline should not be taken with milk products or with other substances containing calcium, magnesium, iron, or aluminum because these ions chelate with tetracyclines. The plasma half-life of tetracycline is 6-10 hours and a regular dose of tetracycline is 250 mg at 6-hourly intervals. The GCF concentration achieved is 0.4-0.8 μg/ml and plasma concentration achieved is 1.9-2.5 μg/ml 17.

The half-life of doxycycline and minocycline is……………………….

123

Periobasics: A textbook of Periodontics and Implantology
For India Users:
Buy Now
For International Users:

After a regular oral dose, tetracycline achieves a GCF concentration of 2 to 10 μg/mL. The state of renal function affects the clearance of tetracycline so it should not be given to patients whose renal function is compromised. On the other hand, doxycycline is excreted predominantly in the feces so can be given to patients with compromised renal function. Similarly, minocycline is metabolized primarily in the liver and excreted in feces so can be given to patients with compromised renal function.

Antibacterial spectrum:

Tetracyclines are broad-spectrum antibiotics effective against many Gram-positive and Gram-negative bacteria. Tetracycline has been shown to be very effective in the treatment of aggressive periodontitis because Aggregatibacter actinomycetemcomitans, the prime pathogen of aggressive periodontitis is very susceptible to this antibiotic. Because of the tissue invasion property of this microorganism, it is difficult to eliminate just by mechanical debridement alone. It has been demonstrated that 1g/day systemic administration of tetracycline for 3-6 weeks along with adequate plaque control can halt the progression of aggressive periodontitis 22, 23.

Other pharmacological properties of tetracyclines:

In addition to the antimicrobial effect, tetracyclines also exhibit additional pharmacological properties, which are of significance in the management of periodontal diseases. Tetracyclines are capable of inhibiting collagenase 24 due to their property to bind with calcium and zinc ions present on the enzyme. However, this property of tetracyclines depends on the source of the enzyme and type of tetracycline used. Tetracyclines are more effective in neutralizing PMN’s derived MMPs (primarily, MMP8) than fibroblast, epithelial cells and macrophages derived MMPs (primarily MMP1). Doxycycline is most effective tetracycline for collagenase inhibition. Sub anti-microbial dose of doxycycline has been used clinically for host modulation (for detail read chapter 14 “Host response modulation therapeutic agents for periodontal diseases”).

Further, tetracyclines may also act as oxygen radical scavengers produced by PMN’s. These oxygen radicals have an ability to activate latent collagenase, thus tetracyclines can prevent the oxidative activation of latent collagenase 25. Along with inhibition of neutrophil-derived collagenase tetracyclines also exert their anti-proteolytic property by preventing the formation of neutrophil-derived reactive oxygen species, i.e., hypochlorous acid, hydrogen peroxide, and hydroxyl radicals 26. Tetracyclines also prevent bone resorption due to their anti-collagenase and anti-proteolytic activity. They have been shown to inhibit osteoblast-derived collagenases and have a modifying effect on osteoclasts 27. Tetracyclines inhibit bone resorption induced by parathyroid hormone 28.

Tetracyclines have been shown to exhibit anti-inflammatory properties. This property of tetracyclines is attributed to their ability to suppress of PMN activity, scavenging reactive oxygen species and blocking eicosanoid synthesis (especially, PGE2) by inhibiting phospholipase A2 activity 29. Tetracyclines are also used as root bio-modification agents. It has been observed that pre-treatment of root surface with tetracycline during surgical procedures enhances fibroblast attachment and colonization on the root surface 30, 31.

Mechanism of resistance:

There are primarily three mechanisms, by which bacteria become resistant to tetracyclines: limiting the access of tetracyclines to ribosomes, protection of ribosomes from the drug and tetracycline inactivation by bacteria.

Limiting the access of tetracyclines to ribosomes:

This is accomplished by two mechanisms: reduced uptake of tetracyclines and tetracycline efflux. The entry of tetracyclines in a bacterial cell is required to achieve their antibacterial action via hindering protein synthesis. Some bacteria reduce the entry of tetracyclines by altering the porin proteins (e.g. OmpF) present in the cell wall. It results in increased bacterial resistance up to 6 to 18 fold 32, 33. The second mechanism is expelling the tetracyclines out of the bacterial cell. It is one of the most common mechanisms adopted by microorganisms for drug resistance. Two major efflux systems used for drug efflux are specific exporters and transporters conferring multidrug resistance. These mechanisms are genetically encoded on chromosomes. The genes of the specific efflux system are often associated with mobile genetic elements, whereas genes for multidrug resistance systems are commonly located on the bacterial chromosome. The mobile genetic elements can be transferred to other bacteria 34.

Protection of ribosomes from drug:

This is a less common mechanism of bacterial resistance to antibiotics as compared to drug efflux mechanism where specific proteins are synthesized in the cytoplasm which interact and associate with the ribosomes making them insensitive to tetracyclines 35, 36. There are multiple ribosome protection resistance genes which have been characterized and sequenced, including tet(M), tet(O), tet(Q) and tet(S) 37-40.

Tetracycline inactivation:

Resistance genes have been identified in the bacterial cells, which confer resistance to tetracycline by enzymatic degradation of the drug. This type of resistance was first discovered by Guiney et al. (1989) 41 from the obligate anaerobe Bacteroides fragilis.

Clinical use in periodontal diseases:

As already stated, soft tissue invasion by periodontal pathogens makes them inaccessible to mechanical periodontal therapy. Thus, mechanical treatment may not predictably eliminate putative pathogens such as A. actinomycetemcomitans from the subgingival area. It has been demonstrated that tetracyclines have the ability to concentrate in the periodontal tissues and inhibit the growth of A. actinomycetemcomitans 42-44. Furthermore, sub-inhibitory concentrations of tetracyclines have been shown to reduce adherence and co-aggregation of species including P. gingivalis and P. intermedia during plaque formation 45, 46.

However, because of increased bacterial resistance against tetracyclines, a combination of metronidazole and penicillin has been preferred by some investigators. As tetracyclines exhibit host modulation properties, many chemically modified tetracyclines have been used for this purpose. The sub-antimicrobial dose of doxycycline has been used in many clinical trials for host modulation.

Adverse effects:

The most significant unwanted effect of tetracycline is its incorporation into calcifying tissues which causes permanent discoloration of teeth 47. So, it should not be prescribed in children below the age of eight years and in pregnant patients as it gets deposited in teeth and bone. Photosensitivity is another side effect of these drugs so patients are advised to avoid sunlight. The gastrointestinal disturbance is one more side effect which can be seen in some patients. Patients may complain of nausea, vomiting, abdominal discomfort or diarrhea. This is caused primarily due to disturbance of normal gastrointestinal flora. Tetracyclines have also been implicated in causing pseudomembranous colitis. Rarely, hypersensitive reactions may also be encountered with tetracyclines. Cross hypersensitivity to other members of the drug family is present, so the patient should not be given any drug from tetracycline group of drugs if such reaction is encountered. If prolonged therapy with heavy dosage is given there are chances of renal and hepatic damage.

Metronidazole:

Metronidazole is a nitroimidazole compound with bactericidal, amoebicidal and trichomoncidal properties. It was initially developed as an antiprotozoal agent. Presently, in dentistry, it is a widely used drug for the treatment of Gram-negative, anaerobic periodontal infections. The exact mode of action has not been fully elucidated but disruption of DNA and inhibition of nucleic acid synthesis seems to be the primary actions of this drug.

Pharmacokinetics:

The commonly used dosage of metronidazole is 200 mg three times a day for 3 days. However, in severe infections 400 mg, twice a day dosage may be used for the duration of 5 days. The drug may be given orally or parenterally. The drug is rapidly absorbed after oral administration and it reaches its peak plasma concentration within 1-2 hours. The plasma half-life of the drug is 8 hours. The drug is metabolized in the liver and has good tissue penetration. It diffuses across the blood-brain barrier, crosses the placenta and appears in the saliva and breast milk. The drug is not significantly bound to plasma proteins. The drug is excreted in urine in an unchanged form.  The drug is contraindicated in patients with evidence of or a history of blood dyscrasias, the presence of active organic disease of the central nervous system and in the case of hypersensitive reaction to the drug. It should also not be given in the first trimester of pregnancy, since it crosses the placenta and rapidly enters the fetal circulation. Although, its teratogenic potential has not been well established but such a possibility cannot be excluded.

Antibacterial spectrum:

The drug is bactericidal and effectively kills many anaerobic Gram-negative bacilli including Bacteroides fragilis and other Bacteroides species and also Fusobacterium species. Along with Gram-negative bacteria, the drug is effective against various Gram-positive bacteria including Clostridium species, Eubacterium, and anaerobic Streptococcus. As already stated, the drug is very effective against pathogenic protozoa, including Trichomonas vaginalis and other Trichomonads and the causative organisms of acute ulcerative gingivitis.

Mechanism of resistance:

Metronidazole has been extensively used but acquired resistance to this drug has rarely been reported. Two mechanisms proposed for increased resistance include reduced entry of the drug into the cell and reduced intracellular reduction of the drug. Production of 5-nitroimidazole reductase which enzymatically reduces the 5-nitroimidazole to a 5-amino derivative is another mechanism by which the drug molecules are inactivated. The genes which code for this enzyme include nimA, nimB, nimC and nimD.

Clinical uses in periodontal diseases:

Metronidazole has been used extensively in………………….

123

Periobasics: A textbook of Periodontics and Implantology
For India Users:
Buy Now
For International Users:

Adverse effects:

The commonly associated adverse effects with the use of this drug are gastrointestinal disturbance, nausea, vomiting, dyspepsia, diarrhea, and constipation. A metallic, sharp unpleasant taste is a common finding. A moderate and transient leukopenia may occasionally be observed in some patients. The most serious neurological side effects of this drug include convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy. Metronidazole can interact with various drugs including coumarin anticoagulants, disulfiram, alcohol, cyclosporine, phenobarbital, phenytoin etc. Hypersensitivity reaction to this drug have also been reported.

Macrolides:

Macrolides are primarily used to control infections caused by Gram-positive bacteria. First macrolide used was erythromycin which is in clinical use for more than 45 years now. Newer macrolides include azithromycin, spiramycin, roxithromycin, and clarithromycin. These drugs inhibit RNA-dependent protein synthesis, resulting in bacteriostatic antimicrobial activity.

Pharmacokinetics:

Erythromycin:

Chemically, erythromycin is C37H67NO13 (Figure 47.4). It is destroyed by gastric acid, except if administered with a protective enteric coating. The drug has a good oral bioavailability but it is affected by food in different ways depending on the formulation used. The absorption of the drug is decreased with the base forms and increased with the estolate form. The drug has a short half-life of 1-1.5 hours and is administered 6 hourly. Erythromycin is highly bound to plasma proteins and gets well distributed in body tissues. The drug is metabolized in the liver with the help of hepatic cytochrome P-450 isozymes. Around 20% of the oral dose of erythromycin is excreted in urine and rest in feces.

Figure 47.4 Chemical structure of erythromycin

Chemical structure of erythromycin

Clarithromycin:

It has a good oral bioavailability which does not depend on the presence of food.  The drug is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin tablets is approximately 50%. The half-life of the drug is 3-7 hours and is administered twice daily. After oral administration, 20-40% of the drug is excreted in urine. In renal dysfunction, the dosage of the drug should be reduced due to decreased drug clearance.

Azithromycin:

Azithromycin is the first of a subclass of macrolides called azalides. Oral bioavailability of the drug is good and is independent of the presence of food. After administering an oral dose of 500 mg, azithromycin is absorbed from the gastrointestinal tract with an absolute bioavailability of 37%. Therapeutic use requires a single dose of 250 mg/day for 5 days after an initial loading dose of 500 mg. Maximum serum concentration of 0.3 – 0.4 µg/mL is achieved in 2 to 3 hours. The penetration of drug is good, owing to its lipid solubility. It has been proposed that this drug penetrates fibroblasts and phagocytes in concentrations 100-200 times greater than that of extracellular compartment. As a result, when these fibroblasts and phagocytes reach the site of inflammation, they release the drug after they rupture during phagocytosis 7. The drug has a long half-life of 40-60 hours which allows its once daily administration. The major route of elimination of unchanged drug following oral administration is biliary excretion.

Spiramycin:

The absolute oral bioavailability of spiramycin is up to 30-40%. It has got an extensive distribution in tissues. Plasma half-life of this drug is 6.2 to 7.7 hours. The drug is usually less metabolized than some other macrolides. The post-antibiotic effect of spiramycin is prolonged as compared to erythromycin against Staphylococcus aureus. Renal excretion of the drug is up to 4-20%. The major route of drug excretion is via bile.

Roxithromycin:

Roxithromycin is absorbed after oral administration with an absolute bioavailability of approximately 50%. The half-life of the drug is 12 hours and is administered twice daily. It is well bound to plasma proteins (92 to 96%). The drug undergoes limited metabolism in the body, presumably in the liver. Approximately 53% of the oral dose of the drug is excreted through feces, approximately 7% of a dose is excreted in the urine and 13% is eliminated via the lungs.

Antibacterial spectrum:

As already stated, macrolides are primarily active against Gram-positive bacteria including Streptococci, Pneumococci, methicillin sensitive Staphylococci. They have a limited Gram-negative spectrum which includes Bordetella and Campylobacter.

Mechanism of resistance:

There are primarily three mechanisms by which bacterial resistance occurs toward macrolides: efflux of drug from bacterial cell, alterations in ribosomes to prevent effective binding of macrolides and production of enzymes that inactivate the drug.

Efflux of the drug: The efflux pumps effectively transport the drug out of the bacterial cell, thereby providing resistance to the drug. The MEF family genes are associated with the production of these ATP-dependent efflux pumps.

Alterations in ribosomes: The acquisition of one of 21 erm genes by bacteria facilitates the alteration of target ribosomes. The genes code for rRNA methylases which cause methylation of adenine residues in 23S rRNA, preventing the binding of macrolides to the 50S ribosomal subunit. This modification results in the inability of macrolides to bind to these ribosomal units, thus offering resistance to the drug.

Enzymatic inactivation of the drug: Production of enzymes by bacteria which degrade the drug is one quite effective mechanism of drug resistance. It has been reported that production of hydrolases, esterases, transferases and phosphorylases result in the inactivation of various macrolides and related molecules 59.

Clinical used in periodontal diseases:

The clinical application of erythromycin in the management of periodontal diseases is limited because it is not effective against many of the periodontal pathogens and it does not concentrate in GCF.  Use of azithromycin has been recommended in periodontal infections because it is found to concentrate in the inflamed periodontal tissues. Spiramycin has shown beneficial results when used in periodontal infections. It is excreted in high concentrations in saliva 7. Studies have shown improvement in clinical parameters following administration of spiramycin as an adjunct to scaling and root planing 60.

Adverse effects:

The common side effects associated with the use of macrolides includes cough, fever, general feeling of discomfort or illness, hives, hoarseness, skin rashes, itching, joint or muscle pain and shortness of breath. Rarely abdominal pain, dizziness, drowsiness, headache and burning sensation have been reported.

Clindamycin:

Clindamycin is a lincosamide antibiotic synthesized by chemically modifying the naturally occurring lincomycin. This drug is effective against a wide spectrum of facultative and strictly anaerobic bacteria 61, 62. It exerts its antibacterial action by binding to 50 S subunit of bacterial ribosomes thereby inhibiting protein synthesis.  At low concentration, it is bacteriostatic but bactericidal activity is usually achieved with the recommended doses 63.

Pharmacokinetics:

The oral bioavailability of clindamycin is good, with approximately…………………….

123

Periobasics: A textbook of Periodontics and Implantology
For India Users:
Buy Now
For International Users:

Anti-bacterial spectrum:

Clindamycin is primarily active against anaerobic infections including Porphyromonas species, Prevotella species, Bacteroides fragilis group, Veillonella species, and Fusobacterium species, including β-lactamase producing strains. It is also effective against Gram-positive organisms including Actinomyces, Eubacterium, Lactobacillus, Peptostreptococcus, Propionibacterium, and Staphylococcus species, including penicillin-resistant strains 64-66. Along with its anti-bacterial effects clindamycin also reduces adherence of bacteria to the epithelial cells of mucosal surfaces and inhibits the expression of virulence factors 67, 68. It has been shown to inhibit the production of M protein by group A β-hemolytic streptococci.

Clinical use is periodontal diseases:

Many studies have demonstrated the beneficial effects of clindamycin as an adjunct to scaling 69, 70. Clindamycin has been shown to be useful in periodontal infections. Long-term beneficial results have been observed with clindamycin dosage of 600 mg/day for 7 days in refractory periodontitis cases 70-72. One year post treatment results with clindamycin have been shown to be superior when compared to tetracycline 73.

Adverse effects:

Acute pseudomembranous colitis is the major concern with the use of clindamycin. The condition develops as a result of proliferation of the antibiotic resistant Clostridium difficile, which produces metabolites toxic to the gut wall, resulting in colitis. If not treated, it may become fatal. Other adverse effects include nausea, vomiting, abdominal pain or cramps and/or rash. Rarely anaphylaxis, blood dyscrasias, polyarthritis, jaundice have also been reported.

Aminoglycosides:

Aminoglycoside antibiotics are widely used for the treatment of severe Gram-negative infections, often in combination with a β-lactam antibiotic. These are among the most rapidly acting bactericidal drugs available for the treatment of aerobic Gram-negative sepsis. These are bactericidal and perform bacterial killing in dose-dependent manner. It must be noted here that antibiotics with concentration-dependent killing characteristically kill bacteria at a faster rate when drug concentrations are higher. Commonly used aminoglycosides include gentamicin, tobramycin, netilmicin, and amikacin. The mechanism of action of aminoglycosides is via binding to the 30S ribosomal subunit which causes inhibition of protein synthesis and misreading of mRNA, resulting in dysfunctional protein production.

Pharmacokinetics:

Aminoglycosides are primarily used for parenteral therapy. The minimum inhibitory concentration (MIC) of amikacin is more than other aminoglycosides. As the pharmacokinetics of all the aminoglycosides is similar, so more dose of amikacin is required to treat the infection. These are usually administered in 8 hourly doses. These drugs have a reasonable distribution into tissues because of its low protein binding and water solubility. Penetration across the blood brain barrier is poor as is penetration into bronchial secretions. Aminoglycosides are eliminated primarily by glomerular filtration and renal dysfunction is the most important factor affecting the pharmacokinetics of these drugs.

Antibacterial spectrum:

Aminoglycosides have a broad Gram-negative spectrum. Gentamicin is quite effective against various Gram-negative organisms including Pseudomonas aeruginosa. Amikacin is the aminoglycoside most resistant to enzymatic inactivation that is why it must be reserved for treating infections due to microorganisms that are resistant to other aminoglycosides. On the other hand, aminoglycosides have a limited spectrum against Gram-positive organisms. These are active against few Gram-positive bacteria including Staphylococci and Streptococci. Some of the aminoglycosides are active against mycobacteria. However, they have no activity against anaerobes.

Clinical use in periodontal infections:

As already stated aminoglycosides have bactericidal, concentration-dependent killing action and are active against a wide range of aerobic Gram-negative bacilli. However, because these are the drug of choice for serious, life-threatening Gram-negative infections, these should not be used during routine periodontal treatment.

Adverse effects:

All aminoglycosides are potentially ototoxic and nephrotoxic and these adverse effects are more pronounced in patients of advanced age, and those with renal impairment, hearing loss or vestibular impairment. Patients with renal disorders must be kept under observation if these drugs are used.

Fluoroquinolones:

These are nalidixic acid derivatives, having bactericidal activity. Most commonly used drugs in this group are ciprofloxacin, norfloxacin, ofloxacin, levofloxacin, and gatifloxacin. These drugs perform bacterial killing by inhibiting DNA gyrase and topoisomerase IV 74.

Pharmacokinetics:

The oral absorption of fluoroquinolones is rapid. The serum and urine concentrations of these drugs markedly exceed the MICs for many common bacterial pathogens. The drugs are distributed well in tissues. Various drugs in this group have a different half-life, degree of absorption, metabolism, and elimination. In general, quinolones exhibit linear pharmacokinetics, with increases in serum concentrations directly proportional to dose size. The major route of their excretion is renal. However, drug excretion also occurs through the gastrointestinal tract and various other mechanisms.  The GCF concentration of ciprofloxacin is comparable or even reach higher than serum levels.

Antibacterial spectrum:

 Fluoroquinolones are effective against a wide range of both Gram-positive and Gram-negative microorganisms. Ciprofloxacin, levofloxacin, and gatifloxacin, all have excellent in vitro activity against Enterobacteriaceae, fastidious Gram-negative species such as H. influenzae and other Haemophilus species, N. gonorrhoeae, N. meningitides, and M. catarrhalis. They are effective against many established periodontal pathogens including A. actinomycetemcomitans 75. Ciprofloxacin is effectively used against facultative and aerobic Gram-negative rods and cocci.

Clinical use in periodontal diseases:

Studies have been done on evaluating the efficacy of various fluoroquinolones in the elimination of periodontal pathogens.  In a study, it was observed that the treatment with ofloxacin in conjunction with open flap surgery was able to suppress A. actinomycetemcomitans below detectable levels for 12 months 76. Fluoroquinolones have been found beneficial in the treatment of A. actinomycetemcomitans associated periodontitis 77.

Adverse effects:

The common side effects associated with the use of these drugs are nausea, vomiting, diarrhea and painful oral mucosa. Pseudomembranous colitis has been observed in patients taking a high dosage of fluoroquinolones. In some patient hypersensitivity reactions such as rashes, pruritus, urticaria, pigmentation and edema of lips have been reported. Ciprofloxacin should not be prescribed to children and young individuals due to potential joint problems.

Vancomycin:

It is a glycoprotein antibiotic used primarily to………………..

123

Periobasics: A textbook of Periodontics and Implantology
For India Users:
Buy Now
For International Users:

Pharmacokinetics:

The drug is administered as a short-term (1 hour) intravenous infusion because it is not appreciably absorbed orally. The plasma half-life of the drug is 6-12 hours. Protein binding of the drug ranges from 10-50%. Factors that affect the overall activity of vancomycin include its tissue distribution, inoculum size, and protein-binding effects. The drug effectively penetrates most of the tissues but is somewhat dependent on the degree of inflammation present. Vancomycin is primarily eliminated via the renal route, with >80%-90% recovered unchanged in urine within 24 h after the administration of a single dose.

Anti-bacterial spectrum and use in periodontal diseases:

Vancomycin is primarily a drug of choice for the elimination of methicillin-resistant strains of Staphylococcus aureus and is generally reserved for serious drug-resistant Gram-positive infections. Its use during routine periodontal therapy is not recommended. Vancomycin is used prophylactically for the prevention of infective endocarditis in patients with prosthetic heart valves.

Adverse effects:

An allergic reaction may occur due to vancomycin which may manifest as pruritus and flushing on the face (Red man’s syndrome), neck, and shoulders. Other adverse effects include reversible neutropenia and thrombocytopenia. Nephrotoxicity may occur if a higher dose of the drug is given or the drug is given in combination with aminoglycosides. Rarely, ototoxicity has been observed, especially when the drug is combined with other ototoxic drugs.

Table47.3 Mechanism of action and adverse effects of various antimicrobial agents

Antimicrobial agent
Mechanism of action
Bacteriostatic/bactericidal
Frequent adverse effect
Less frequent and rare adverse effect
PenicillinDisruption of cell wall
Synthesis
BactericidalSkin rashes (ampicillin and amoxicillin), allergic reaction, diarrhea (ampicillin and amoxicillin)Gastrointestinal (GI) disturbance, hemolytic anemia, pseudomembranous colitis, platelet dysfunction (high dose only). Rarely, Anaphylactic shock, seizures (high dose only), hepatotoxic reaction, agranulocytosis, renal damage, hypokalemia, and/or hypernatremia (high dose only)
CephalosporinDisruption of cell wall synthesisBactericidalThrombophlebitis (IV admin), serum sickness (after prolong parenteral admin), diarrheaAllergic reaction, GI disturbance, hemostatic disturbance. Rarely, Anaphylactic shock, hemolytic anemia, hepatic dysfunction, blood dyscrasia, nephrotoxicity, pseudomembranous colitis, seizure
ErythromycinInhibits RNA-dependent protein synthesisBacteriostaticGastrointestinal disturbanceStomatitis, cholestatic hepatitis (erythromycin estolate). Rarely, Allergic reaction, pseudomembranous colitis, hemolytic anemia, transient hearing loss
TetracyclineDisruption of protein synthesisBacteriostaticGastrointestinal disturbance, hypoplasia, and staining of calcifying tissueMalabsorption, superinfection, photosensitivity (demeclocycline), vestibular toxicity (minocycline), azotemia and other metabolic disturbance during renal insufficiency (except doxycycline), hepatoxicity during pregnancy or renal dysfunction. Rarely, allergic reaction, blood dyscrasias, increased intracranial pressure, pseudomembranous colitis, diabetes insipidus (demeclocycline), prolonged bleeding time, fixed drug eruption, blurred vision
ClindamycinDisruption of protein synthesisBacteriostatic Diarrhea, allergic reactionsPseudomembranous colitis. Rarely, hepatoxicity, Blood dyscrasia, esophageal ulceration
VancomycinDisruption of cell wall synthesisBactericidal Thrombophlebitis, chills, feverNephrotoxicity, ototoxicity (auditory mainly), and neutropenia. Rarely, Peripheral neuropathy, allergic reactions including anaphylaxis (mainly skin rashes), hypotension (rapid IV injection)
MetronidazoleDisruption of nucleic acid synthesisBactericidalGI disturbance, headache, dry mouthDiarrhea, insomnia, stomatitis, paresthesias. Rarely, Encephalopathy, ataxia, pseudomembranous colitis, leukopenia, pancreatitis

Combination therapy

Beneficial results can be obtained by combining antibacterial agents. It broadens the……………

123

Periobasics: A textbook of Periodontics and Implantology
For India Users:
Buy Now
For International Users:

This combination has been used extensively for the treatment of A. actinomycetemcomitans associated localized juvenile periodontitis, Papillon-Lefevre syndrome periodontitis, adult type periodontitis, rapidly progressing periodontitis, generalized advanced periodontitis, and refractory periodontitis 15, 78-80. This combination has also been shown to be effective in the elimination of P. intermedia 15, 78, 79 and in cases of aggressive periodontitis 81. In refractory periodontitis cases, a combination of Metronidazole-Augmentin has been shown to be effective 82.

Commonly used drugs and drug combinations for various periodontal conditions 3, 6, 83, 84

Periodontal condition
Drug/drug combination
Chronic periodontitisTetracycline, Doxycycline, Metronidazole, Clindamycin, Amoxicillin + Clavulanic acid (Augmentin), Azithromycin, Metronidazole +
Amoxicillin, Spiramycin.
Aggressive periodontitisTetracycline, Doxycycline, Minocycline, Metronidazole, Amoxicillin + Clavulinic acid (Augmentin), Metronidazole + Amoxicillin.
Necrotizing periodontal diseasesAmoxicillin, metronidazole and combination of amoxicillin + metronidazole.
Periodontal abscessAmoxicillin, Azithromycin, Clindamycin, Metronidazole + Amoxicillin

Local drug delivery

The local administration of the antibacterial agents has many advantages over the systemic drug delivery. There has been much advancement in the field of local drug delivery in periodontal therapy. A detailed description of agents used in local drug delivery has been given in chapter 48, “Local drug delivery in periodontics”.

Other anti-microbial agents used in periodontal therapy

There are many other anti-microbial agents used in periodontal therapy including chlorhexidine, povidone iodine, Listerine, sodium hypochlorite, hydrogen peroxide etc. Chlorhexidine is the most common agent used for plaque control. It is considered as a gold standard for chemical plaque control. Subgingival irrigation with chlorhexidine and povidone-iodine has been shown to reduce the subgingival bacterial load. A detailed description of these agents has been given in 46 “Chemical plaque control”

Other chemotherapeutic agents used in periodontal therapy are host response modulation agents. These agents modulate the host response in such a way that the host-mediated connective tissue destruction is prevented. These agents have been discussed in detail in “Host response modulation therapeutic agents in periodontics”.

Conclusion

Application of chemotherapeutic agents in the overall management of periodontal diseases has been a part of the standard periodontal treatment plan for many years now. However, periodontal infections involve a variety of pathogens with different antimicrobial sensitivities and resistance patterns. The reduction of this bacterial load by mechanical plaque control is the primary treatment in preventing periodontal disease progression and the chemotherapeutic agents can only be used as an adjunct to this treatment. The antimicrobial regimen must be determined carefully depending on the clinical presentation of the disease and the most probable microorganisms involved. Furthermore, unnecessary use of these agents may result in the development of resistance to ensure the survival of that species which then may become difficult to treat. Hence, a judicial use of antimicrobials is recommended.

Periobasics: A textbook of Periodontics and Implantology
For India Users:
Buy Now
For International Users:

References:

References available in the hard copy of the website

Periobasics: A textbook of periodontics and implantology

Leave a Reply

You must be logged in to post a comment.