Antimicrobial compounds include antibacterial, antiviral, antifungal and antiprotozoal agents. All of these, apart from the last group, are prescribed in dentistry.
All antimicrobials demonstrate selective toxicity; that is, the drug can be administered to humans with reasonable safety while having a marked lethal or toxic effect on specific microbes. The corollary of this is that all antimicrobials have adverse effects on humans and should therefore be used rationally and only when required.
Antimicrobial therapy aims to treat infection with a drug to which the causative organism is sensitive. Antimicrobials can be administered on a 'best-guess' basis, with a sound knowledge of the:
■ infectious disease
■ most probable pathogen
■ usual antibiotic sensitivity pattern of the pathogen.
This is called empirical antibiotic therapy and contrasts with rational antibiotic therapy in which antibiotics are administered after the sensitivity of the pathogen has been established by culture and in vitro testing in the laboratory. In general, empirical therapy is undertaken in the majority of situations encountered in dentistry.
Bacteriostatic and bactericidal antimicrobial agents
Antimicrobial agents are classically divisible into two major groups: bactericidal agents, which kill bacteria; and bacteriostatic agents, which inhibit multiplication without actually killing the pathogen. However, the distinction is rather hazy and is dependent on factors such as the concentration of the drug (e.g., erythromycin is bacteriostatic at low concentrations and bactericidal at high concentrations), the pathogen in question and the severity of infection. Further, host defence mechanisms play a major role in the eradication of pathogens from the body, and it is not essential to use bactericidal drugs to treat most infections. A bacteriostatic drug that arrests the multiplication of pathogens and so tips the balance in favour of the host defence mechanisms is satisfactory in many situations.
Mode of action of antimicrobials
Antimicrobial agents inhibit the growth of or kill microorganisms by a variety of mechanisms. In general, however, one or more of the following target sites are involved:
■ cell wall
■ ribosomes
■ cytoplasmic membrane
■ nucleic acid replication sites.
A summary of the mode of action of commonly used antimicrobials is given in Table 7.1 and Fig. 7.1.
Principles of antimicrobial therapy
Antimicrobial agents should be prescribed on a rational clinical and microbiological basis. In general, therapy should be considered for patients when one or more of the following conditions are present:
■ fever and an acute infection
■ spreading infection without localization
■ chronic infection despite drainage or debridement
■ infection in medically compromised patients
■ cases of osteomyelitis, bacterial sialadenitis and some periodontal diseases, such as acute ulcerative gingivitis and localized aggressive periodontitis (previously localized juvenile periodontitis).
(Note: this is not an exhaustive list.)
Choice of drug
The choice of drug is strictly dependent upon the nature of the infecting organisms and their sensitivity patterns. However, in a clinical emergency such as septicaemia or Ludwig angina, antimicrobial agents must be prescribed empirically until laboratory tests are completed. In general, another antimicrobial drug should be prescribed if the patient has had penicillin within the previous month because of the possible presence of penicillin-resistant bacterial populations previously exposed to the drug.
Table 7.1 Cellular target sites of antimicrobial drugs commonly used in dentistry
|
Target site |
Drug |
Bactericidal/static |
Comments |
|
Cell wall |
β-Lactams, e.g., penicillin, ampicillin, cephalosporin, cloxacillin Bacitracin (topical) |
Cidal Cidal |
Interfere with cross-linking of cell wall peptidoglycan molecules Inhibits peptidoglycan formation |
|
Ribosomes |
Erythromycin, fusidic acid (topical) Tetracycline |
Statica or cidalb Static |
Interfere with translocation, thus inhibiting protein synthesis Interferes with attachment of transfer RNA, thus inhibiting protein synthesis |
|
Cytoplasmic membrane |
Polyenes, e.g., nystatin, amphotericin |
Static |
Disrupt yeast cell membrane |
|
Nucleic acid replication |
Metronidazole Idoxuridine, aciclovir |
Cidal Cidal |
Interferes with DNA replication Interfere with DNA synthesis in DNA viruses |
|
aLow concentrations. bHigh concentrations. |
|||
Fig. 7.1 Mode of action of some common antimicrobial agents. DHF, Dihydrofolic acid; PABA, para-aminobenzoic acid (or β-aminobenzoic acid); THF, tetrahydrofolic acid.
Spectrum of activity of antimicrobial agents
Antimicrobial agents can be categorized as broad-spectrum and narrow-spectrum antibiotics, depending on their activity against a range of Gram-positive and Gram-negative bacteria. For example, penicillin is a narrow-spectrum antibiotic with activity mainly against the Gram-positive bacteria, as is metronidazole, which acts almost entirely against strict anaerobes and some protozoa.
Broad-spectrum antimicrobials (e.g., tetracyclines, ampicillins) are active against many Gram-positive and Gramnegative bacteria, and they are often used for empirical or 'blind' treatment of infections when the likely causative pathogen is unknown. This unfortunately leads to 'abuse' of broad-spectrum agents, with the consequent emergence of resistance in organisms that were originally sensitive to the drug. The spectrum of activity of some broad-spectrum and narrow-spectrum antimicrobial agents is shown in Table 7.2.
Table 7.2 Spectrum of activity of some commonly used antimicrobial agents
|
Drug |
Spectrum |
|
Phenoxymethylpenicillin (penicillin V) |
1. Aerobic Gram-positives (e.g., streptococci, pneumococci, β-lactamase-negative) 2. Anaerobic Gram-positives (e.g., anaerobic streptococci) 3. Anaerobic Gram-negatives (e.g., most Bacteroides, fusobacteria, Veillonella) |
|
Penicillinase-resistant penicillins (e.g., flucloxacillin) |
All the above, including β-lactamase- producing staphylococci |
|
Ampicillin |
As for penicillin, also includes Haemophilus spp. |
|
Cephalosporins |
As for penicillin, also includes some coliforms |
|
Erythromycin |
Gram-positives mainly but some anaerobes not susceptible at levels obtained by oral administration |
|
Tetracycline |
Broad-spectrum. Many Gram-positives and -negatives |
|
Metronidazole |
All strict anaerobes are sensitive, including some protozoa. Of questionable value for facultative anaerobes |
Combination therapy
Whenever possible, a single antimicrobial agent should be used to reduce the:
■ incidence of possible side effects
■ emergence of resistant bacteria
■ drug costs.
However, there are certain clinical situations where a combination of drugs is valuable: for example, to achieve a high bactericidal level when treating patients with infective endocarditis; the use of gentamicin and metronidazole in the empirical treatment of a patient with serious abdominal sepsis; and combination therapy in the management of tuberculosis. In dentistry, combination therapy should be avoided as far as possible.
Antimicrobial prophylaxis
Antimicrobial prophylaxis is the use of a drug to prevent colonization or multiplication of microorganisms in a susceptible host. The value of prophylaxis depends upon a balance between:
■ the benefit of reducing the infection risk and consequent secondary morbidity
■ the possible toxic effects to the host, including alterations of the host commensal flora
■ the cost-effectiveness.
When used appropriately, prophylaxis can reduce morbidity and the cost of medical care. Irrational prophylaxis leads to a false sense of security, increased treatment cost and the possible emergence of resistant flora.
Aims
The aims of antimicrobial prophylaxis are:
■ prevention of host colonization by virulent agents, for example, chemoprophylaxis (with rifampicin) given to close contacts of patients with meningococcal meningitis (see Chapter 25)
■ prevention of implantation and/or implanted organisms reaching a critical mass sufficient to produce infection, for example, antimicrobial prophylaxis in infective endocarditis patients before surgical procedures
■ prevention of the emergence of latent infection, for example, antifungal agents given either intermittently or continuously to prevent candidal infection in human immunodeficiency virus (HlV)-infected patients.
In dentistry, antibiotics are used as prophylactic agents before dental or surgical treatment of patients who:
■ are at risk of infective endocarditis (see Chapter 24)
■ have facial fractures or compound skull fractures, and cerebral rhinorrhoea
■ are immunocompromised
■ have recently received radiotherapy to the jaws (as they succumb to infection as a result of severe ischaemia of the bone caused by radiotherapy)
■ have prosthetic hip replacements, ventriculoatrial shunts, insertion of implants or bone grafting.
However, the benefit of prophylactic antimicrobial therapy in most of the aforementioned situations has been recently reviewed and most authorities consider prophylactic antibiotics unnecessary, due to the threat of the emergence of antibiotic- resistant flora. If prophylactic antibiotics are prescribed, then the advantages and disadvantages must be carefully weighed for each individual clinical situation.
Prescribing an antimicrobial agent
The following should be considered before any antimicrobial agent is prescribed.
Is there an infective aetiology?
When there is no good clinical evidence of infection, antimicrobial therapy is unnecessary, except in prophylaxis (discussed earlier).
Have relevant specimens been taken before treatment?
Appropriate specimens should be collected before drug therapy is begun as the population of pathogens may be reduced, and therefore less easily isolated, if specimens are collected after antimicrobial agents have been taken. Further, the earlier the specimens are taken, the more likely it is that the results will be useful for patient management.
When should the treatment be started?
In patients with life-threatening infections, for example, Ludwig angina, intravenous therapy should generally be instituted immediately after specimen collection. Antimicrobial therapy may be withheld in chronic infections until laboratory results are available (e.g., actinomycosis).
Which antimicrobial agent?
Consider the pharmacodynamic effects, including toxicity, when choosing a drug from a number of similar antimicrobial agents that are available to treat many infections (see the following section). An adequate medical history, especially in relation to past allergies and toxic effects, should be taken before deciding on therapy.
Pharmacodynamics of antimicrobials
Dosage
Antimicrobial agents should be given in therapeutic doses sufficient to produce a tissue concentration greater than that required to kill or inhibit the growth of the causative microorganism(s).
Duration of treatment
Ideally, treatment should continue for long enough to eliminate all or nearly all of the pathogens, as the remainder will, in most instances, be destroyed by the host defences. Conventionally, this cannot be precisely timed, and standard regimens last for some 3-5 days, depending on the drug. However, a short-course, high-dose therapy of certain antibiotics such as amoxicillin is as effective as a conventional 5-day course. The other advantages of short courses of antimicrobial agents are good patient compliance and minimal disturbance to commensal flora, leading to an associated reduction in side effects such as diarrhoea.
Route of administration
In seriously ill patients, drugs should be given by the parenteral route to overcome problems of absorption from the intestinal tract. All antimicrobial agents given by mouth must be acid stable.
Distribution
The drug must reach adequate concentrations at the infective focus. Some antibiotics, such as clindamycin, that penetrate well into bone are preferred in chronic bone infections; in meningitis, a drug that penetrates the cerebrospinal fluid should be given.
Excretion
The pathway of excretion of an antimicrobial agent should be noted. For example, drugs metabolized in the liver, such as erythromycin estolate, should not be given to patients with a history of liver disease because they may cause hepatotoxicity, leading to jaundice.
Toxicity
Most antimicrobials have side effects and the clinician should be aware of these (for examples, see the following section on antibacterial agents).
Drug interactions
Drug interactions are becoming increasingly common owing to the extensive use of a variety of drugs. For instance, antibiotics such as penicillin and erythromycin can significantly reduce the efficacy of some oral contraceptives, and antacids can interfere with the action of tetracyclines. All clinicians should therefore be aware of the drug interactions of any antimicrobial they prescribe. The major drug interactions of antimicrobials commonly used in dentistry are given in Table 7.3.
Failure of antimicrobial therapy
Consideration should be given to the following potential problems if an infection does not respond to drugs within 48 h:
■ inadequate drainage of pus or debridement
■ inappropriateness of the antimicrobial agent, including bacterial resistance to the drug, dosage and drug interactions
■ presence of local factors such as foreign bodies, which may act as reservoirs of reinfection
■ impaired host response, for example, in patients who are immunocompromised by drugs or HIV infection
■ poor patient compliance
■ possibility of an unusual infection or that the disease has no infective aetiology
■ poor blood supply to tissues.
Antibiotic resistance in bacteria
Emergence of drug resistance in bacteria is a major problem in antibiotic therapy and depends on the organism and the antibiotic concerned. Whereas some bacteria rapidly acquire resistance (e.g., Staphylococcus aureus), others rarely do so (e.g., Streptococcus pyogenes). Resistance to some antibiotics is virtually unknown (e.g., metronidazole), but strains resistant to others (e.g., penicillin) readily emerge.
Table 7.3 Some drug interactions of antimicrobials commonly used in dentistry
|
Drug affected |
Drug interacting |
Effect |
|
Penicillins |
Probenecid, neomycin |
May potentiate the effect of penicillin. Reduced absorption |
|
Erythromycin |
Theophylline |
Increase theophylline levels, leading to potential toxicity |
|
Cephalosporins |
Gentamicin Furosemide (Lasix) |
Additive effect leading to nephrotoxicity Possible increase in nephrotoxicity |
|
Tetracycline |
Antacids, dairy products, oral iron, zinc sulphate |
Reduced absorption |
|
Metronidazole |
Alcohol |
‘Antabuse’ effect |
|
Fluconazole oral (antifungal agent) |
Disulfiram, phenobarbital, phenytoin Warfarin |
Reduced effect Slows warfarin metabolism and increases warfarin effect |
Antibiotic resistance develops when a progeny of resistant bacteria emerges. As they will be at a selective advantage over their sensitive counterparts, and as long as the original antibiotic is prescribed, the resistant strains can multiply uninhibitedly (e.g., hospital staphylococci with almost universal resistance to penicillin). Such antibiotic resistance can be divided into:
■ primary (intrinsic) resistance: where the organism is naturally resistant to the drug; that is, its resistance is unrelated to contact with the drug (e.g., resistance of coliforms to penicillin)
■ acquired resistance: due to either mutation within the same species (chromosomal resistance) or gene transfer between different species via plasmids (extrachromosomal resistance; see Fig. 3.6)
■ cross-resistance: when resistance to one drug confers resistance to another chemically related drug (e.g., bacteria resistant to one type of tetracycline may be resistant to all other types of tetracycline).
Mechanisms of antibiotic resistance (Table 7.4)
Inactivation of the drug
This is very common, for example, production of β-lactamase by staphylococci. The enzyme, which is plasmid coded, destroys the β-lactam ring responsible for the antibacterial activity of penicillins.
Altered uptake
The amount of drug that reaches the target is either reduced or completely inhibited (e.g., tetracycline resistance in Pseudomonas aeruginosa). This can be either due to altered permeability of the cell wall or to pumping of the drug out of the cell (efflux mechanism).
Modification of the structural target of the drug
Resistance to some penicillins due to loss or alteration of penicillin-binding proteins (PBPs) of the organism (e.g., penicillin resistance in Streptococcus pneumoniae).
Altered metabolic pathway
This results in bypassing the reactive focus of the drug, for example, a few sulphonamide-resistant bacteria can use preformed folic acid and do not require extracellular p-aminobenzoic acid (a folic acid precursor) for the eventual synthesis of nucleic acids.
Table 7.4 Plasmid-mediated antibiotic resistance
|
Antibiotic |
Mechanism of resistance |
|
β-Lactams |
β-Lactamase breaks down the β-lactam ring to an inactive form |
|
Aminoglycosides |
Modifying enzymes cause acetylation, adenylation, phosphorylation |
|
Chloramphenicol |
Acetylation of the antibiotic to an inactive form |
|
Erythromycin, clindamycin |
Methylation of ribosomal RNA prevents antibiotic binding to ribosomes |
|
Sulphonamides, tetracycline |
Alteration of cell membrane decreases permeability to the antibiotic |
Emergence of drug-resistant bacteria and the role of the dental practitioner
Emergence of antibiotic-resistant organisms is now a catastrophic threat of global concern. This is accentuated by the extremely slow discovery of new antimicrobial agents due to the associated massive research and developmental costs, difficulties in conducting extensive clinical trials and a litigious society.
It has been estimated that if new and effective antibiotics are not discovered, the emerging wave of antibiotic-resistance organisms could cause 10 million deaths every year globally by 2050, costing the global economy US$ 100 trillion.
Antibiotics account for the vast majority of medicines prescribed by dentists. In the UK, for instance, dentists prescribe between 7% and 11% of all common antibiotics, which accounts for 7% of all community prescriptions of antimicrobials. Furthermore, it has been estimated that globally approximately one-third of all outpatient antibiotic prescriptions are unnecessary. Hence dentists must be aware of general principles of minimizing the emergence of drug resistance and rational therapy, which include:
■ as far as possible resort to rational, rather than empirical antibiotic therapy (see previous discussion)
■ appropriate dosage and duration to maintain an adequate level of antibiotic in the tissues to inhibit the offending pathogens and the evolving mutant strains
■ avoidance of polypharmacy, where two antibiotics with similar properties are prescribed instead of a single antibiotic
■ however, in situations not usually encountered in dentistry, such as in the management of tuberculosis, it is imperative to administer two drugs, one of which administered alone will result in the emergence of resistant strains
■ usage of proven traditional drugs as first-line therapy in preference to newer, more effective and fashionable drugs (e.g., initial use of polyenes for candidal infections instead of triazoles).
Antimicrobials commonly used in dentistry
Although a large array of antimicrobial agents have been described and are available to medical practitioners, only a limited number of these are widely prescribed by dental practitioners. The following therefore is an outline of the major antimicrobials (antibacterials, antifungals and antivirals) used in dentistry.
Antibacterial agents
Penicillins
Penicillins are the most useful and widely used antimicrobial agents in dentistry. A wide array of penicillins have been synthesized by incorporating various side chains into the β-lactam ring (Table 7.5). The spectrum of activity and indications for the use of these penicillins vary widely. The more commonly used penicillins such as phenoxymethylpenicillin (penicillin V) are described in the following section in some detail. Others, such as the carboxypenicillins (carbenicillin and ticarcillin) and ureidopenicillins (azlocillin and piperacillin), which are active against Gram-negative organisms, are rarely used in dentistry, except for amoxicillin.
Table 7.5 Types of penicillin
|
Group |
Type of penicillin |
|
Narrow spectrum |
Benzylpenicillin Phenoxymethylpenicillin Procaine penicillin Benzathine penicillin |
|
Broad spectrum |
Ampicillin Amoxicillin Esters of ampicillin |
|
Penicillinase resistant |
Methicillin Flucloxacillin |
|
Antipseudomonal |
Piperacillin Mezlocillin |
The commonly used penicillins are remarkably non-toxic but all share the problem of allergy. Minor reactions such as rashes are common, while severe reactions, especially anaphylaxis, although rare, can be fatal. Allergy to one penicillin is shared by all the penicillins and, in general, the drug should not be given to a patient who has had a reaction to any member of this group. Some 10% of patients sensitive to penicillin show cross-reactivity to cephalosporins.
Phenoxymethylpenicillin (penicillin V)
Administration
Oral, as it is acid resistant.
Mode of action
Bactericidal; inhibits cell wall synthesis by inactivating the enzyme transpeptidase, which is responsible for cross-linking the peptidoglycan cross walls of bacteria; an intact β-lactam ring is crucial for its activity.
Spectrum of activity
Effective against a majority of a-haemolytic streptococci and penicillinase-negative staphylococci. Aerobic Gram-positive organisms, including Actinomyces, Eubacterium, Bifidobacterium and Peptostreptococcus spp. are sensitive, together with anaerobic Gram-negative organisms such as Bacteroides, Prevotella, Porphyromonas, Fusobacterium and Veillonella species. The majority of Staphylococcus aureus strains, particularly those from hospitals, are penicillinase producers and hence resistant to penicillin. (A small minority of a-haemolytic streptococci, and some Aggregatibacter actinomycetemcomitans strains implicated in aggressive periodontitis, are resistant.)
Resistance
Very common, owing to the β-lactamase produced by bacteria, which inactivates the drug by acting on the β-lactam ring.
Indications
As this drug can be administered orally, it is commonly used by dental practitioners in the treatment of acute purulent infections, post-extraction infection, pericoronitis and salivary gland infections.
Pharmacodynamics
Phenoxymethylpenicillin is less active than parenteral ben- zylpenicillin (penicillin G) because of its erratic absorption from the gastrointestinal tract. Therefore, in serious infections, phenoxymethylpenicillin could be used for continuing treatment after one or more loading doses of benzylpenicillin, when clinical response has begun.
Toxicity
Virtually non-toxic; may cause severe reactions in patients who are allergic; anaphylaxis may occur very rarely. Other uncommon reactions include skin rashes and fever. Despite these drawbacks, it is one of the cheapest and safest antibiotics.
Benzylpenicillin (penicillin G)
Administration
Intramuscular, intravenous.
Indications
Useful in moderate to severe infections (e.g., Ludwig angina) as its parenteral administration results in rapid, high and consistent antibiotic levels in plasma.
Toxicity
Chances of allergy developing are increased by injection, and it is obligatory to ascertain the hypersensitivity status of the patient before the drug is administered. Benzylpenicillin may cause convulsions after high doses by intravenous injection or in renal failure.
Broad-spectrum penicillins susceptible to staphylococcal penicillinase: ampicillin and amoxicillin
Administration
Oral (amoxicillin absorption is better than ampicillin), intramuscular, intravenous.
Spectrum of activity
Similar to penicillin but effective against a broader spectrum of organisms, including Gram-negative organisms such as Haemophilus and Proteus spp. Amoxicillin and ampicillin have similar antibacterial spectra.
Resistance
One drawback of amoxicillin is its susceptibility to β-lactamase, but if potassium clavulanate is incorporated with amoxicillin, the combination (co-amoxiclav) is resistant to the activity of β-lactamase (Fig. 7.2).
Indications
Ampicillin is sometimes used in the empirical treatment of dentoalveolar infections when the antibiotic sensitivity patterns of the causative organisms are unknown. In dentistry, amoxicillin is the drug of choice for prophylaxis of infective endocarditis in a restricted group of patients undergoing surgical procedures and scaling (see Chapter 24). A short course of high-dose amoxicillin (oral) has been shown to be of value in the treatment of dentoalveolar infections.
Fig. 7.2 Amoxicillin is broken down by p-lactamase of bacteria to penicilloic acid. If potassium clavulanate (a product of Streptomyces clavuligerus) is incorporated with amoxicillin, it inhibits the β-lactamase activity. The combination drug is known as co-amoxiclav.
Toxicity
Associated with a higher incidence of drug rashes than penicillin, and hence should not be administered to patients with infectious mononucleosis (glandular fever) or lymphocytic leukaemia (because of the probability of a drug rash). Nausea and diarrhoea are frequent, particularly on prolonged administration; superinfection and colonization with ampicillin-resistant bacteria, such as coliforms and fungi, may also occur. The incidence of diarrhoea is less with amoxicillin.
Isoxazolyl penicillins: methicillin, cloxacillin and flucloxacillin
Administration
Oral, intramuscular, intravenous.
Spectrum of activity
Narrow-spectrum antistaphylococcal penicillins relatively resistant to β-lactamase produced by Staphylococcus aureus.
Indications
The main use of cloxacillin and flucloxacillin is in the treatment of confirmed infections due to β-lactamase-producing
Staphylococcus aureus.
Toxicity
These penicillins are safe and non-toxic, even when used in high doses.
Sensitivity
When these antibiotics were introduced, almost all strains of Staphylococcus aureus were sensitive to these drugs. However, methicillin-resistant Staphylococcus aureus (MRSA) strains are now emerging widely, and hence these drugs should not be used indiscriminately.
Other penicillins
Other groups of penicillins, such as carboxypenicillins (e.g., ticarcillin), acylureidopenicillins (e.g., piperacillin) and amidi- nopenicillins (e.g., mecillinam), are not routinely prescribed in dentistry, and hence are not described here.
Cephalosporins, cephamycins and other β-lactams
This group of drugs now includes more than 30 different agents and newer agents are being manufactured each year. All cephalosporins are β-lactams similar to penicillin but are relatively stable to staphylococcal penicillinase; the degree of stability varies with different cephalosporins. The group includes cephalosporins (cefotaxime, cefuroxime, cephalexin and cephradine), cephamycins (cefoxitin), monobactams (aztreonam) and carbapenems (imipenem and meropenem).
Administration
Cephradine and cephalexin, which can be given by mouth, and cephaloridine belong to the first generation of cephalosporins and are used in dentistry. The vast majority of cephalosporins are given parenterally; hence they are virtually restricted to hospital use.
Spectrum of activity
Broad-spectrum; active against both Gram-positive and Gramnegative bacteria, although individual agents have differing activity against certain organisms.
Indications
Few absolute indications. In dentistry, cephalosporins should be resorted to as a second line of defence, depending on culture and antibiotic-sensitivity test results.
Toxicity
Some 10% of penicillin-sensitive patients demonstrate crosssensitivity; allergic reactions, including urticaria and rashes; possibly nephrotoxicity. Another disadvantage is that oral bacteria, including streptococci, may develop cross-resistance to both penicillins and cephalosporins. Hence cephalosporins are not suitable alternatives for a patient who has recently had penicillin.
Erythromycin
The most popular member of the macrolide group of antibiotics.
Administration
Oral, intravenous.
Mode of action
Bacteriostatic.
Spectrum of activity
Similar, though not identical, to that of penicillin and thus the first choice in dentistry for treating penicillin-allergic patients. In addition, Haemophilus influenzae, Bacteroides, Prevotella and Porphyromonas spp. are sensitive. Erythromycin has the added advantage of being active against β-lactamase-producing bacteria. Not usually used as a first-line drug in oral and dental
infections because obligate anaerobes are not particularly sensitive.
Toxicity
A few serious side effects, the main disadvantage being that high doses (given for prophylaxis of infective endocarditis) cause nausea; prolonged use (>14 days) of erythromycin estolate may be hepatotoxic.
Clindamycin
Administration
Oral, intravenous or intramuscular.
Mode of action
Inhibits protein synthesis by binding to bacterial ribosomes.
Spectrum of activity
Similar to that of erythromycin (with which there is partial cross-resistance) and benzylpenicillin; in addition, it is active against Bacteroides spp.
Indications
Mainly reserved, as a single dose, for prophylaxis of infective endocarditis in patients allergic to penicillin; particularly effective in penetrating poorly vascularized bone and connective tissue.
Toxicity
Mild diarrhoea is common. Although rare, the most serious side effect of clindamycin, which can sometimes be fatal, is pseudomembranous (antibiotic-associated) colitis, especially in the elderly patients and in combination with other drugs. The colitis is due to a toxin produced by Clostridium difficile, an anaerobe resistant to clindamycin. Allergy to these drugs is extremely rare, and hypersensitivity to penicillin is not shared by them.
Tetracyclines
Formerly one of the most widely used antibiotic groups owing to their very broad spectrum of activity and infrequent side effects. Their usefulness has decreased as a result of increasing bacterial resistance. They remain, however, the treatment of choice for infections caused by intracellular organisms such as chlamydiae, rickettsiae and mycoplasmas, as they penetrate macrophages well. A range of tetracyclines is available, although tetracycline itself remains the most useful for dental purposes.
Administration
Mostly oral.
Mode of action
Bacteriostatic; interfere with protein synthesis by binding to bacterial ribosomes.
Spectrum of activity
Have a wide spectrum of activity against oral flora, including Actinomyces, Bacteroides, Propionibacterium, Aggregatibacter, Eubacterium and Peptococcus spp.
Indications
In dentistry, tetracyclines are used with some success as adjunctive treatment in localized aggressive periodontitis (formerly localized juvenile periodontitis); they are effective against many organisms associated with these diseases (see Chapter 33). They are also useful as mouthwashes to alleviate secondary bacterial infection associated with extensive oral ulceration, especially in compromised patients.
Pharmacokinetics
Widely distributed in body tissues, and incorporated in bone and developing teeth (Fig. 7.3); particularly concentrated in gingival fluid. Absorption of oral tetracycline is decreased by antacids, calcium, iron and magnesium salts.
Toxicity
Because of the deposition of tetracycline within developing teeth, its use should be avoided in children up to 8 years of age and in pregnant or lactating women; otherwise, unsightly tooth staining may occur. Diarrhoea and nausea may occur after oral administration, as a result of disturbance to bowel flora. However, when reduced dosages are used, even for prolonged periods (e.g., for acne), few side effects are apparent. Serious hepatotoxicity may occur with excessive intravenous dosage.
Metronidazole
The exquisite anaerobic activity of this drug, which was first introduced to treat protozoal infections, makes it exceedingly effective against strict anaerobes and some protozoa.
Administration
Oral, intravenous, rectal (suppositories).
Mode of action
Bactericidal; it is converted by anaerobic bacteria into a reduced, active metabolite, which inhibits DNA synthesis.
Spectrum of activity
Active against almost all strict anaerobes, including Bacteroides spp., fusobacteria, eubacteria, peptostreptococci and clostridia.
Fig. 7.3 Tetracycline stains in a deciduous tooth visualized by polarizing light microscopy. Each yellow band represents an episode of drug administration.
Indications
The drug of choice in the treatment of acute necrotizing ulcerative gingivitis; also used, either alone or in combination with penicillin, in the management of dentoalveolar infections.
Pharmacokinetics
Well absorbed after oral (or rectal) administration; widely distributed and passes readily into most tissues, including abscesses, and crosses the blood-brain barrier into cerebrospinal fluid. The drug is metabolized in the liver.
Toxicity
Minor side effects of metronidazole include gastrointestinal upset, transient rashes and metallic taste in the mouth. Metronidazole interferes with alcohol metabolism and, if taken with alcohol, may cause severe nausea, flushing and palpitations (disulfiram-type effect). It potentiates the effect of anticoagulants and, if used for more than a week, peripheral neuropathy may develop, notably in patients with liver disease; allergenicity is very low.
Sulphonamides and trimethoprim
These drugs interfere with successive steps in the synthesis of folic acid (an essential ingredient for DNA and RNA synthesis). They are widely used in combination because of in vitro evidence of synergism.
Co-trimoxazole
A combination of sulfamethoxazole and trimethoprim in a 5 : 1 ratio.
Administration
Oral, intramuscular, intravenous.
Mode of action
Bacteriostatic (see previous text).
Spectrum of activity
Broad; active against both Gram-positive and Gram-negative bacteria.
Indications
Use now mainly confined to infections in HIV-infected persons.
Pharmacokinetics
A major advantage of sulphonamides is their ability to penetrate into the cerebrospinal fluid; contraindicated in pregnancy or liver disease.
Fusidic acid
A narrow-spectrum antibiotic with main activity against Grampositive bacteria, particularly Staphylococcus aureus. Angular cheilitis associated with Staphylococcus aureus is a specific indication for the use of fusidic acid in the form of a topical cream. A small percentage of Staphylococcus aureus strains show resistance to fusidic acid.
Other antimicrobial agents
The foregoing describes the major antimicrobials prescribed by dentists; the student is referred to recommended texts for details of other antibiotics, such as aminoglycosides and antituberculous drugs, and a comprehensive review of this subject.
Antifungal agents
In contrast to the wide range of antibacterial agents, the number of effective antifungals is limited. This is because selective toxicity is much more difficult to achieve in eukaryotic fungal cells, which share similar features with human eukaryotic cells. Polyenes and the azoles are the most commonly used antifungals in dentistry. Nystatin and amphotericin are polyene derivatives; miconazole and fluconazole are two examples of a variety of azole antifungals currently available (Table 7.6).
Polyenes
Nystatin
Administration
Too toxic for systemic use; not absorbed from the alimentary canal, and hence used to prevent or treat mucosal candidiasis; it is available in the form of pastilles, ready-mixed suspensions, ointments and powder.
Mode of action
Polyene binds to the cytoplasmic membrane of fungi, altering cell wall permeability, with resultant leakage of cell contents and death; in very low doses, it is fungistatic.
Table 7.6 Common antifungal agents and their activity
|
Drug group |
Example |
Target |
Mechanism |
|
Polyenes |
Nystatin |
Cell membrane function |
Bind to sterols in cell membrane, causing leakage of cell constituents and cell death |
|
Amphotericin |
|||
|
Azoles |
Miconazole Ketoconazole Fluconazole |
Cell membrane synthesis |
Inhibit ergosterol synthesis |
|
DNA analogues |
Flucytosine |
Nucleic acid synthesis |
Inhibit DNA synthesis and central protein synthesis |
Indications
Widely used in the treatment of oral candidiasis. Patient compliance is superior with the flavoured pastille formulation, as opposed to the bitter-tasting oral suspension or lozenge.
Spectrum of activity
Nystatin resistance in candidiasis is unknown.
Toxicity
Nausea, vomiting and diarrhoea are rare side effects; no adverse effects have been reported when the topical route is used.
Amphotericin
Amphotericin is the other polyene group antifungal. It is used essentially in the same way as nystatin; lozenges, ointment and oral suspensions are available. As with nystatin, its absorption from the gut is minimal on topical administration. Amphotericin is the drug of choice for the treatment of systemic candidiases and other exotic mycoses (e.g., histoplasmosis, coccidioidomycosis).
Azoles
Miconazole
Administration
An imidazole available as an oral gel or cream.
Mode of action
This drug, like other imidazoles, acts by interfering with the synthesis of chemicals needed to form the plasma membrane of fungi, resulting in leakage of cell contents and death.
Indications
Its dual action against yeast and staphylococci is useful in the treatment of angular cheilitis.
Spectrum of activity
Both fungicidal and bacteriostatic for some Gram-positive cocci, including Staphylococcus aureus. Resistance only rarely occurs.
Fluconazole
Fluconazole is a triazole drug that is highly popular because of its wide spectrum of activity on yeasts and other fungi. Specifically used to prevent Candida infection in HIV-infected individuals as intermittent or continuous therapy.
Administration
Oral; because of its long half-life, it is administered once a day, so patient compliance is good.
Mode of action
See previous discussion; good concentrations are found in saliva and crevicular fluid.
Indications
As a second-line antifungal for recalcitrant oral Candida infections; drug of choice for prophylaxis of oral and systemic candidal infections in HIV-infected patients.
Pharmacokinetics
Weak protein binding, water soluble, long half-life.
Toxicity
Minor: gastrointestinal irritation, allergic rash, elevation of liver enzymes (common to all azoles). Interacts with anticoagulants, terfenadine, cisapride and astemizole.
Itraconazole and posaconazole
Two other azoles with properties similar to fluconazole; useful for candidiasis in HIV disease.
New antifungal agents
Echinocandins
A new class of antifungals that disrupts cell wall integrity by inhibiting cell wall polysaccharide. The intravenous agent, caspofungin, available commercially, belongs to this group and is effective against systemic candidiasis and invasive aspergillosis; no specific role in dentistry.
Terbinafine
A new orally administered allylamine drug that blocks fungal ergosterol synthesis; effective in the management of dermatophyte infections, including nail infections; may be given intermittently with azoles for recalcitrant fungal infections; no role in dentistry.
Antiviral agents
Few antiviral drugs with proven clinical efficacy are available, in contrast to the great range of successful antibacterial agents. The shortage of antivirals is mainly due to the difficulty of interfering with the viral activity within the cell without damaging the host. Most antiviral agents achieve maximum benefit if given early in the disease. Immunocompromised patients with viral infections generally benefit from active antiviral therapy, as these infections may spread locally and systemically.
Other problems associated with the therapy of virus infections are:
■ The incubation period of most viral infections is short, and by the time the patient shows signs of illness, the virus has already done most of the damage. Furthermore, laboratory diagnosis of viral infections takes several days. However, advances in the rapid viral diagnostic methods using molecular techniques should help overcome this problem.
■ Viruses that are latent in cells and not actively replicating (e.g., herpesviruses in the trigeminal ganglion) are immune to antivirals.
Aciclovir is the major antiviral drug prescribed in dentistry.
Aciclovir
Aciclovir is an efficient, highly selective antiviral agent useful in the treatment of primary as well as secondary herpetic stomatitis and herpes labialis.
Administration
Topical (cream), oral (tablets, suspensions), intravenous.
Mode of action
Aciclovir blocks viral DNA production at a concentration of some thousand times less than that required to inhibit host cell DNA production (Fig. 7.4).
Indications
Topical aciclovir (5% cream) can be prescribed for recurrent herpetic ulcers; primary herpetic gingivostomatitis can be treated with either aciclovir cream or tablets. Treatment must be started in the prodromal phase (when there is a local tingling or burning sensation). Application at later stages of infection will reduce the length, discomfort and the viral shedding period correspondingly. Aciclovir tablets or oral suspension may be given for severe herpetic stomatitis or herpes zoster.
An alternative agent for herpetic ulcerations is penciclovir cream.
Fig. 7.4 Mode of action of aciclovir in herpesvirus-infected cells.
Key facts
• All antimicrobials demonstrate selective toxicity and should be used only rationally and when necessary.
• Antibiotic therapy can be either empirical, when the antibiotic is prescribed on a ‘best-guess’ basis, or rational, when the prescription is dictated by the known antibiotic sensitivity of the offending pathogen.
• Antimicrobials are classified by their target sites and their chemical family.
• There are four possible target areas of antimicrobials: the cell wall, ribosomes (protein synthesis), cytoplasmic membrane and the nucleic acid replication sites.
• Whenever possible, use a single antimicrobial drug (and not multiple agents) to reduce the incidence of possible side effects, emergence of resistant bacteria and the drug costs.
Antibiotic resistance in bacteria can be either primary (intrinsic) or acquired; acquired resistance arises due to either mutation or gene transfer.
Major mechanisms of antibiotic resistance include the production of drug-destroying enzymes, altering the drug uptake and target site modification.
Selective toxicity is much more difficult to achieve with antifungal agents because the eukaryotic fungal cells share similar features with human eukaryotic cells.
The shortage of antiviral agents is mainly due to the difficulty of interfering with the viral activity within the cell without damaging the host.
Review questions (answers on p. 363)
Please indicate which answers are true, and which are false.
7.1 Empirical antimicrobial treatment:
A. should be reviewed by susceptibility testing whenever possible
B. can be life-saving
C. can promote the emergence of resistant species
D. is superior to rational antibiotic treatment
E. should be based on the susceptibility and resistance patterns of organisms in the locality
7.2 Antimicrobial prophylaxis:
A. is often practised in dentistry
B. dosage and duration are similar as for a treatment regime
C. does not promote emergence of drug-resistant bacteria
D. induces changes in the normal flora
E. may prevent the emergence of latent infections
7.3 Which of the following statements are true?
A. amoxicillin has a broader antibacterial spectrum than penicillin
B. amoxicillin is resistant to β-lactamase
C. amoxicillin is the drug of choice in endocarditis prophylaxis during dental procedures
D. amoxicillin is effective against methicillin-resistant Staphylococcus aureus (MRSA)
E. amoxicillin is not recommended for the treatment of pharyngitis
7.4 Which of the following statements are true?
A. tetracycline causes discolouration of developing teeth
B. tetracyclines have a wide-spectrum activity against oral flora
C. oral absorption of tetracycline is enhanced by antacids
D. diarrhoea is a common adverse effect of tetracycline
E. tetracycline is not recommended for children
7.5 Which of the following statements are true?
A. metronidazole is bactericidal
B. metronidazole is effective against anaerobes and facultative anaerobes alike
C. metronidazole acts on the ribosome
D. metronidazole is the drug of choice for treating acute necrotizing ulcerative gingivitis
E. metronidazole synergizes the 'hangover' effect of alcohol
7.6 Which of the following statements are true?
A. fluconazole is the drug of choice in systemic candidal infections in human immunodeficiency virus (HIV)- infected patients
B. fluconazole is administered orally
C. fluconazole acts on the fungal cell membrane
D. fluconazole is the first-line drug for oral candidal infections
E. fluconazole may cause hepatotoxicity
7.7 Aciclovir cream in herpes labialis:
A. is best given during the prodromal stage of the disease
B. kills latent viruses in neural ganglia
C. inhibits viral DNA synthesis
D. local application permanently cures herpetic stomatitis
E. has reduced patient compliance due to profound adverse effects
Further reading
Brook, I., Lewis, M. A. O., Sandor, G. K. B., et al. (2005). Clindamycin in dentistry: More than just effective prophylaxis for endocarditis?
Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics, 100, 550-558.
Ellepola, A. N. B., & Samaranayake, L. P. (2000). Oral candidal infections and antimycotics. Critical Reviews in Oral Biology and Medicine, 11, 172-198.
Government of UK. (2016). Dental Antimicrobial Stewardship: Toolkit. Available from: https://www.gov.uk/guidance/dental -antimicrobial-stewardship-toolkit.
Samaranayake, L. P., & Johnson, N. (1999). Guidelines for the use of antimicrobial agents to minimise the development of resistance. International Dental Journal, 49, 189-195.
Scottish Dental Clinical Effectiveness Programme. Drug prescribing for dentistry (3rd ed.). Available from: http://www.sdcep.org.uk/ wp-content/uploads/2016/03/SDCEP-Drug-Prescribing-for -Dentistry-3rd-edition.pdf.