Clinical Implications of Systemic Antibacterial Agents

34 Pages·2014·1.67 MB·English

by  Free

Pharmacology of Systemic Antibacterial Agents:
Clinical Implications
Leena Palomo, DDS, MSD; Géza T. Terézhalmy, DDS, MA
Continuing Education Units: 3 hours
Online Course: www.dentalcare.com/en-US/dental-education/continuing-education/ce450/ce450.aspx
Disclaimer: Participants must always be aware of the hazards of using limited knowledge in integrating new techniques or
procedures into their practice. Only sound evidence-based dentistry should be used in patient therapy.
Participants in this course will be introduced to evidence-based information related to the microbiology
of odontogenic infections, the pharmacology of systemic antibacterial agents, and the rationale for the
selection of an antibacterial agent for the treatment of odontogenic infections.
Conflict of Interest Disclosure Statement
• Dr. Palomo reports no conflicts of interest associated with this work.
• Dr. Terézhalmy has done consulting work for Procter & Gamble and is a member of the dentalcare.com
Advisory Board.
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by the Academy of General Dentistry. The formal continuing education programs of this
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7/31/2017. Provider ID# 211886
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Overview
Participants in this course will be introduced to evidence-based information related to the microbiology of
odontogenic infections, the pharmacology of systemic antibacterial agents, and the rationale for the selection
of an antibacterial agent for the treatment of odontogenic infections.
Learning Objectives
Upon completion of this course, the dental professional should be able to:
• Discuss the microbiology of odontogenic infections.
• Discuss the pharmacology of systemic antibacterial agents.
• Select the most appropriate antibacterial agent to treat an odontogenic infection.
• Discuss potential ADEs associated with the administration of antibacterial agents.
Course Contents the normal flora establish symbiotic relationships
• Introduction (mutualism, commensalisms, or parasitism) with
• Microbiology of Odontogenic Infections their human host and each other.2,3
• Pharmacology of Systemic Antibacterial Agents
Inhibitors of Bacterial Cell Wall Synthesis Factors that modify or shift the balanced
Inhibitors of DNA Synthesis or Integrity environment of the normal flora (age, altered
Inhibitors of Transcription or Translation anatomy, diet, local and systemic conditions,
• Strategies for the Treatment of Odontogenic or pharmacotherapy) may predispose an
Infections individual to infection.4,5 Infection, the invasion
Primary Dental Care and multiplication of microorganisms in body
Adjunctive Antibacterial Chemotherapy tissues, results in cellular injury due to competitive
Prophylactic Antibacterial Chemotherapy metabolism, toxin production, or immune-mediated
• Prescription-precautions Associated with reactions. An infection may be autogenous,
Antibacterial Agents caused by the body’s normal flora; or it may be
Antibacterial Drug-resistance a cross-infection, related to the proliferation of
Gastrointestinal Distress transient organisms.6
Hypersensitivity Reactions
Cardiovascular Effects Microbiology of Odontogenic Infections
Central Nervous System Effects Predicated on their metabolic characteristics, i.e.,
Oral Candidiasis their metabolic demand for oxygen, bacteria are
Antibacterial Drugs and Pregnancy classified as aerobic, facultative, or anaerobic.
Antibacterial Drugs and Nursing Morphologically, they are characterized as cocci
Drug-drug Interactions or bacilli (rods). Based on Gram’s Method of
• Conclusion staining (Box 1), bacteria are further classified
• Course Test Preview as gram-positive or gram-negative. The distinct
• References staining properties of bacteria are related to their
• About the Authors architectural and biochemical differences.7
Introduction Gram-positive bacteria possess a thick
The human fetus is free of microorganisms.1 peptidoglycan cell wall interspersed with
After initial exposure at birth, most organisms are lipoteichoic acid underlain by the cytoplasmic
soon eliminated, but others become permanently membrane (Figure 1).8 Gram-negative bacteria
established and the dynamic process of have an outer membrane with lipopolysaccharides
colonization begins. The adult body harbors a and a lipoprotein layer underlain by a thin
dense, diverse, indigenous flora that includes peptidoglycan layer and the cytoplasmic
bacteria, viruses, fungi and protozoa. Interaction membrane (Figure 2).8 The ability of antibacterial
between these various microbial ecosystems agents to diffusion into bacteria is also affected by
determines the normal flora. Microorganisms of these structural differences.
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Box 1. Gram’s Method of staining.7
Figure 1. Gram-positive bacteria.
Figure 2. Gram-negative bacteria.
Images 1&2, modified from Kasmar AG, Hooper D. Pharmacology of bacterial
infections: cell wall synthesis. In Golan DE, Tashjian, Jr. AH, Armstrong EJ, Armstrong
AW. Ed. Principles of pharmacology. The pathophysiologic basis of drug therapy. 2nd
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ed. 2008. Wolters Kluwer/Lippincott Williams & Wilkins. Baltimore, MD.
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Figure 3. Gram-negative organisms.
Figure 4. Mixed gram-positive and gram negative organisms.
During staining, crystal violet interacts with iodine acidic environment and decreased oxygenation
forming a complex. Acetone extracts lipids from to support the growth and proliferation of its
the outer membrane, cell wall, and cytoplasmic members. Ultimately, facultative and anaerobic
membrane of bacteria.7 The damage to gram- gram-positive and gram-negative cocci and bacilli
negative organisms is more extensive and they predominate in all types of odontogenic infections
lose their crystal violet-iodine complexes, i.e., (Table 1).9-31
they are decolorized; and when counterstained
with safranin, they appear red (Figure 3).7 Gram- Pharmacology of Systemic Antibacterial
positive bacteria retain their crystal violet-iodine Agents
complexes and appear deep purple (Figure 4).7 Pharmacological strategies are predicated
on targeting differences between prokaryotic
An average adult harbors at least 300 oral bacterial and eukaryotic host cells. Selective
bacterial species and more than 700 strains of toxicity can be achieved by (1) attacking targets
bacteria have been isolated from test cases.9-11 unique to bacteria, (2) attacking targets in bacteria
Most odontogenic infections are polymicrobial. similar but not identical to those in host cells, and
The number of strains per infection ranges from (3) attacking targets that are shared, but vary
1 to 10 with an average number of 4 isolates.9,12-24 in importance between bacteria and host cells
The predominant flora creates an ecosystem (Figure 5).32 Drugs targeting unique differences
of synergism by elaborating a more favorable are the least toxic to host cells.
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Table 1. Bacteria detected in odontogenic infections.26,27
Figure 5. Mechanisms of action of antibacterial agents.
Based on Harbison H, Rose HS, Coen DM, Golan DE. Principles of antibacterial and antineoplastic pharmacology. In
Golan DE, Tashjian, Jr. AH, Armstrong EJ, Armstrong AW. Ed. Principles of pharmacology. The pathophysiologic basis
32
of drug therapy. 2nd ed. 2008. Wolters Kluwer/Lippincott Williams & Wilkins. Baltimore, MD.
Antibacterial agents are either bactericidal or Inhibitors of Bacterial Cell Wall Synthesis
bacteriostatic. Bactericidal drugs attack targets Most pathogenic bacteria have a cell wall that
essential for bacterial survival, e.g., inhibitors provides tensile strength and maintains intracellular
of cell wall synthesis and most inhibitors of osmotic pressure. Its synthesis progresses in
DNA synthesis and integrity.32 Bacteriostatic three steps: (1) monomers are synthesized in
drugs attack targets that are necessary for the cytoplasm from amino acid and sugar building
bacterial growth but not for survival, e.g., most blocks; (2) Bactoperol transfers the monomers
inhibitors of transcription and translation.32 Since across the cytoplasmic membrane where they
bacteriostatic drugs block bacterial replication, are polymerized into linear peptidoglycan chains;
they antagonize the effects of bactericidal drugs. finally, (3) transpeptidase cross-links peptidoglycan
chains into a three-dimensional mat (Figure 6).8
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Figure 6. Bacterial cell wall synthesis.
Modified from Kasmar AG, Hooper D. Pharmacology of bacterial infections: cell wall synthesis. In Golan DE, Tashjian, Jr. AH, Armstrong EJ,
Armstrong AW. Ed. Principles of pharmacology. The pathophysiologic basis of drug therapy. 2nd ed. 2008. Wolters Kluwer/Lippincott Williams &
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Wilkins. Baltimore, MD.
A number of drugs inhibit cell wall synthesis. potassium and broad-spectrum amoxicillin and
Most important are Vancomycin, which targets amoxicillin with clavulanic acid have the requisite
monomer polymerization; and the β-lactams, spectra to be considered as empirical options
e.g., penicillins and cephalosporins, which block in treating odontogenic infections.10,42 However,
polymer cross-linking.8,33-41 β-lactam antibacterial neither narrow-spectrum nor broad-spectrum
agents also activate autolysins. Autolysins punch penicillins are active against β-lactamase
holes in bacterial cell wall and disrupt its integrity.8 producing bacteria; and certain β-lactamases
Transpeptidase antagonism and autolysis prevent produced by bacteria now confer resistance to
bacterial self-maintenance, i.e., remodeling and clavulanic acid as well.8,43-51
repair; and replication.
Penicillin V potassium and amoxicillin formulations
Vancomycin are not inactivated by gastric acid and also have
Vancomycin is bactericidal in susceptible the advantage that they may be given with meals.
organisms. It is primarily effective against aerobic They are widely distributed to most tissues and
gram-positive cocci and bacilli.8,33,36,37 It does have body fluids, cross the placenta and they are
activity against some anaerobic gram-positive, excreted into breast milk. The penicillins undergo
but not against gram-negative bacilli. Since hepatic biotransformation. The metabolites and
facultative and anaerobic gram-positive and the unchanged fraction of the drugs are excreted
gram-negative cocci and bacilli predominate in all rapidly in individuals with normal renal function.
types of odontogenic infections, Vancomycin does
not have the requisite spectrum to be considered Cephalosporins
an empirical option in treating odontogenic The cephalosporins are bactericidal in susceptible
infections. organisms.8,35,40,41,52 Most are primarily active
against aerobic gram-positive cocci and bacilli.
Penicillins Second generation cephalosporins (e.g., cefaclor)
Penicillins are bactericidal in susceptible have an overlapping spectra with those of
organisms.8,38,39 Narrow-spectrum penicillin V penicillin V potassium and amoxicillin formulations
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Figure 7. Folate synthesis.
Modified from Harbison H, Rose HS, Coen DM, Golan DE. Principles of antibacterial and antineoplastic pharmacology.
In Golan DE, Tashjian, Jr. AH, Armstrong EJ, Armstrong AW. Ed. Principles of pharmacology. The pathophysiologic
32
basis of drug therapy. 2nd ed. 2008. Wolters Kluwer/Lippincott Williams & Wilkins. Baltimore, MD.
and are more β-lactamase resistant than the aerobic gram-positive and gram-negative
first generation cephalosporins. However, cocci and bacilli.53-57 The newer agents (e.g.,
cephalosporins, in general, offer no therapeutic moxifloxacin) have some anaerobic activity.10,58,59
advantage over penicillins as empirical options in Fluoroquinolones are indicated for the treatment
treating odontogenic infections. of infections with designated, susceptible
bacteria and are not empirical options in treating
Inhibitors of DNA Synthesis or Integrity odontogenic infections.55-57
Cell wall inhibitors cannot kill all bacteria because
some bacteria lack a cell wall. Other bacteria Metronidazole
have unique structures that inherently resist the A metabolite of metronidazole directly binds
accumulation or action of cell wall inhibitors. DNA, causes loss of its helical structure, and
However, bacteria, in preparation for cell division, effects strand breakage.50,60,61 It is bactericidal in
must replicate their double stranded DNA. To susceptible organisms. Metronidazole is active
facilitate replication, topoisomerase type II, a against most obligate anaerobes, but lacks
bacterial DNA gyrase, must first unwind and clinically relevant activity against obligate aerobes
separate, and then reassemble the original DNA and facultative anaerobes.61,62 Metronidazole,
during the process.53 in combination with an agent active against
aerobic/facultative organisms (e.g., penicillin),
In the replication process, bacteria must is an empirical option in treating odontogenic
synthesize folate. Its synthesis begins with infections.61,62
the formation of dihydropteroic acid from
pteridine and para-aminobenzoic acid (PAPA), a Metronidazole is well absorbed after oral
reaction catalyzed by dihydropteroate synthase administration and reaches peak plasma
(Figure 7).32 Dihydropteroic acid and glutamate concentrations in 1 to 2 hours.61 It is distributed
condense to form dihydrofolate (DHF).32 to most body fluids and tissues, including bone;
Dihydrofolate reductase (DHFR) reduces DHF crosses the placenta, and reaches concentrations
to tetrahydrofolate (THF). THF is an essential in saliva and human milk similar to those found in
cofactor in the synthesis of DNA, RNA, and plasma.61 Metronidazole is metabolized by hepatic
proteins (Figure 7).32 oxidation and glucuronic conjugation.61 The major
route of elimination of metronidazole and its
Fluoroquinolones metabolites is via the kidneys.61
Fluoroquinolones block topoisomerase type
II activity and disrupt the integrity of bacterial Antimetabolites
DNA.53-57 They are bactericidal in susceptible Sulfamethoxazole (SMX) and trimethoprim
organisms and are primarily active against (TMP), block succeeding steps in folate synthesis
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(see Figure 7).32,63 SMX-TMP formulations are The P-site initially is occupied by the fMet-tRNA
bacteriostatic in susceptible organisms. It has complex. As the next charged tRNA binds to
activity against a broad spectrum of aerobic gram- the 70S ribosomal unit, but before it is allowed
positive and gram-negative organisms, but it is not to enter the unoccupied A-site, the rRNA must
active against anaerobes.63 SMX-TMP does not confirm that the charged tRNA carries the specific
have the requisite spectrum to be considered an amino acid called for by the mRNA codon.54 If
empirical option in treating odontogenic infections. access is allowed, the rRNA catalyzes the
formation of a peptide bond between the carboxy-
Inhibitors of Transcription or Translation terminal of the fMet residing in the P-site and the
Bacteria, like mammalian cells, must synthesize new amino acid occupying the A-site (Figure 9).53
proteins for self-maintenance and replication. DNA
serves as the “instruction manual;” it provides Once the peptide bond is formed, the tRNA
the information necessary for protein synthesis. originally linked to fMet is ejected from the P-site
The first step in this process is transcription, and the second tRNA located at the A-site, which
the synthesis of a single-stranded ribonucleic is now linked to two amino acids, translocates to
acid (RNA) from the DNA template catalyzed by the unoccupied P-site (Figure 9).53 As the process
RNA polymerase.53 The function of the newly repeats itself, a growing peptide chain emerges
synthesized RNA is translation. from the exit tunnel.53 Translation continues until
a stop codon is encountered in the mRNA and the
In the process of translation, RNA serves three newly synthesized protein is released from the
functions: (1) as messenger RNA (mRNA), it ribosome.53
tells ribosomes which proteins to synthesize; (2)
as transfer RNA (tRNA), it transports specific Tetracyclines
amino acids called for by mRNA codons from the Tetracycline and its semi-synthetic derivatives
cytoplasm to ribosomes; and (3) as ribosomal (e.g., minocycline and doxycycline) bind to 30S
RNA (rRNA), it ensures that the amino acid carried ribosomal subunits and reversibly block the
by the charged tRNA is the one called for by the attachment of the charged tRNA to the aminoacryl
corresponding mRNA codon.53 or A-site.53,64-66 They have bacteriostatic activity
against aerobic gram-positive and gram-negative
Protein synthesis is initiated when the mRNA joins organisms, but in vivo many strains have been
with the 30S ribosomal subunit and tRNA-linked shown to be resistant. Tetracyclines are not
formyl methionine (fMet).53 As the first amino empirical options in the treatment of odontogenic
acid encoded by every bacterial mRNA, fMet infections.
binds the initiation codon on the mRNA.53 Next,
the 30S-fMet-tRNA complex joins with the 50S It is also of note that tetracyclines are
ribosomal subunit to form the complete initiation teratogenic.65-67 They produce higher rates of
complex, i.e., the 70S ribosomal unit, which neuronal-tube defect, cleft palate, and multiple
contains two binding sites, an aminoacyl or A-site congenital abnormalities, e.g., neuronal-tube
and a peptidyl or P-site (Figure 8).53 defect with cardiovascular malformation.
Figure 8. Formation of the 70S ribosomal initiation complex.
Modified from Ryou M, Coen DM. Pharmacology of bacterial infections: DNA replication, transcription, and translation.
In Golan DE, Tashjian, Jr. AH, Armstrong EJ, Armstrong AW. Ed. Principles of pharmacology. The pathophysiologic
53
basis of drug therapy. 2nd ed. 2008. Wolters Kluwer/Lippincott Williams & Wilkins. Baltimore, MD.
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Figure 9. The process of protein synthesis.
Modified from Ryou M, Coen DM. Pharmacology of bacterial infections: DNA replication, transcription, and translation.
In Golan DE, Tashjian, Jr. AH, Armstrong EJ, Armstrong AW. Ed. Principles of pharmacology. The pathophysiologic
53
basis of drug therapy. 2nd ed. 2008. Wolters Kluwer/Lippincott Williams & Wilkins. Baltimore, MD.
Furthermore, tetracyclines induce enamel Macrolides
hypoplasia and discoloration of teeth. Before Macrolides bind 50S ribosomal subunits and block
prescribing tetracycline during pregnancy and/or translocation and peptide movement through the
tooth development the benefits and risks must be exit tunnel.53 They are bacteriostatic in susceptible
considered.65-67 organisms and are active against aerobic gram-
positive cocci and gram-negative bacilli, but
Aminoglycosides anaerobic gram-negative organisms are resistant.
Aminoglycosides (e.g., gentamicin) bind to 30S Azithromycin has an extended spectrum that
ribosomal subunits and induce misreading of includes some anaerobic gram-positive cocci
mRNA codons.53,68,69 They are bactericidal in and gram-negative bacilli and may be considered
susceptible organisms and are active against an empirical option in treating odontogenic
many aerobic and facultative gram-positive and infections.72-78
gram-negative cocci and bacilli, but most species
of streptococci and anaerobic gram-negative Azithromycin is rapidly absorbed after oral
bacilli are resistant.53,68,69 Aminoglycosides do administration. When administered with food,
not have the requisite spectra to be considered however, its rate and extent of absorption is
empirical options in treating odontogenic reduced by about 50%. The drug is widely
infections. distributed throughout the body, accumulating in
high concentration within cells resulting in higher
Clindamycin tissue than plasma concentrations. Azithromycin is
Clindamycin binds to 50S ribosomal subunits and metabolized minimally and is principally eliminated
blocks peptide bond formation between amino as unchanged drug via the liver.
acids located in the P- and A-sites (Figure 8).53,62,70
It has excellent activity against gram-positive Strategies for the Treatment of
aerobes and anaerobes, as well as gram-negative Odontogenic Infections
anaerobes.10,42,71 Consequently, clindamycin Uncomplicated odontogenic infections manifest
has the requisite spectrum to be considered an primarily as caries; and pulpal, periodontal, and
empirical option in treating odontogenic infections. pericoronal problems. Signs and symptoms include
pain, erythema, edema, and difficulty chewing.71,79
Clindamycin is rapidly and almost completely Complicated odontogenic infections reflect the
absorbed after oral administration and reaches extension of an uncomplicated odontogenic infection
peak plasma concentration in about 45 minutes. into surrounding tissues and manifest as cellulitis,
It is widely distributed in body fluids and tissues osteomyelitis, and space infections. Signs and
(including bone). Clindamycin is extensively symptoms include lymphadenitis, trismus, difficulty
metabolized in the liver and its metabolites are swallowing or breathing; and less frequently, fever
excreted primarily by the kidneys. and hypotension.71,79
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Primary Dental Care course of penicillin administered to patients with
acute pain related to a tooth with an amalgam
Reversible Pulpitis restoration without clinical signs of infection,
Patients with reversible pulpitis usually report in the absence of definitive dental care, did
sensitivity or pain in response to hot, cold, not prevent the emergence of clinical signs of
sweets, and mechanical stimuli. Caries in infection within 5 days.89
proximity of the pulp, defective restorations,
exposed dentinal tubules, and traumatic occlusion Acute Apical Periodontitis
appear to be common etiologies. Provoked pain, Irreversible pulpitis and pulpal necrosis (an
described as sharp or intense, primarily reflects asymptomatic complication of irreversible
hyperemia or mild inflammation of the pulp and pulpitis), if left untreated, lead to the spread of
stimulus-induced fluid movement in dentinal irritants and bacteria into periradicular tissues
tubules. and result in acute apical periodontitis. Patients
complain of tenderness or mild to moderate pain
Reversible pulpitis is a reactive process. Caries associated with the apical area of the offending
should be excavated and a temporary sedative tooth. The pain may be intermittent, secondary
restoration placed. Faulty restorations should to manipulation of the tooth, or unprovoked and
be removed and replaced. Exposed dentinal continuous.
tubules should be etched and sealed. To reduce
inflammation and shorten recovery time a The removal of bacteria and their byproducts
disease-modifying analgesic, i.e., a nonsteroidal by debridement and obturation of the root canal
anti-inflammatory drug (NSAIDs) should be system effectively eliminates infection, curtails
prescribed. It is intuitive that antibacterial agents inflammation, and promotes healing. The
would have no effect on clinical outcome. administration of a disease modifying analgesic,
i.e., a NSAID, may shorten recovery time. It has
Irreversible Pulpitis been shown that once the source of infection
Bacteria may gain access to the pulpal system is eliminated, the administration of penicillin
through caries, defective restorations, and provides no statistically significant added benefit.90
exposed dentinal tubules. Other portals may
include apical, lateral, or furcation canals Acute Apical Abscess
associated with advancing periodontal disease. Infection associated with acute apical periodontitis
Pain may be spontaneous, but usually it is in may extend into alveolar bone and soft tissues
response to hot, cold, sweets, and mechanical initiating apical abscess formation. The pain is
stimuli reflects hyperemia or inflammation usually severe, unprovoked and constant. The
secondary to infection, fluid movement in dentinal tooth is usually mobile and the accumulation of
tubules, and increased intrapulpal pressure. fluid in the periodontal ligament space may cause
supraeruption. Manipulation of the tooth causes
Acute dental pain associated with a tooth with exquisite sensitivity and mastication is difficult;
deep carious lesion may reflect a reactive swelling, malaise and fever may be present.
process to caries, but most likely to bacteria
that have infected pulpal tissues.80-85 In case The removal of bacteria and their byproducts
of irreversible pulpitis endodontic debridement by debridement and obturation of the root canal
and obturation of the root canal system is the system effectively eliminates infection, curtails
most predictable method of treatment.86 To inflammation, and promotes healing. The
reduce inflammation and shorten recovery time a swelling, when present, may be drained through
disease-modifying analgesic, i.e., a NSAID should the tooth, by a soft tissue incision, or there may
be prescribed. already be drainage through a naturally occurring
sinus tract. A disease modifying analgesic, i.e., a
In untreated irreversible pulpitis, penicillin does NSAID, may shorten recovery time.
not reduce spontaneous pain, percussion induced
pain, or the amount of analgesics taken by In a prospective study, a five-day course of
patients.87,88 In a prospective study, a five-day penicillin administered to patients with acute
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