ANTI-INFECTIVES IN THE DENTAL
OFFICE: WHAT’S NEW
Crown and Bridge Study Club
April 12, 2019
Dr. Aviv Ouanounou, B.Sc, M.Sc, D.D.S., F.I.C.O.
Assistant Professor, Clinical Sciences (Pharmacology)
Faculty of Dentistry, University of Toronto
Introduction and History
Oral Infections
Antibiotics
Antiviral agents
Antifungal Drugs
Antibiotic Prophylaxis
19 year old female emerg patient presents with intra oral
swelling.
Intra oral exam reveals mod swelling adj to tooth 2.5.
What to do?
Extracted tooth 4.8
Complicated exo– flap and bone removal.
One week post op- pt complains of pain and swelling (you
examine the area and all looks good).
Two weeks later– pain persists, swelling, and the clot is
replaced by granulation tissue at which point you give an
antibiotic and an analgesic.
One month later-- there is mild chronic pain in the area.
Dx
Pt needs an endo on tooth 46.
Med Hx- HBP and Type II Diabetes (mod
controlled).
The patient has had a knee replacement 3
years ago
?
A patient requires antibiotic prophylaxis for
bacterial endocarditis and needs several
appointments for scaling and root planning. How
many days should there be in between each
appointment?
Mr. JS, a 25 year old patient has painful tooth #27
but no swelling , no trismus or increase in
temperature. His general health is Good.
Would you administer antibiotics to him following
an extraction, WHY ?
OROFACIAL
INFLAMMATORY
CONDITIONS
Reversible Pulpitis
Pain is poorly localized
Short duration
Tooth not tender to percussion
Normal radiographic appearance
Irreversible Pulpitis
Spontaneous attacks of pain
Can range from seconds to hrs
Pain is elicited by hot or cold application
In its initial stages pain is elicited by hot then relived by cold
Tooth is tender to percussion
Radiographic appearance
Widening of PDL
Apical periodontitis
An inflammation of the gingivae
Pain is spontaneous
Aggravated by biting
Often tooth is non-vital
Acute or Chronic
Periodontitis
Pain is localized
Dull
Tenderness with the associated teeth
Etiology
Risk factors
Ouanounou, A. 2015. Systemic Antimicrobial Therapy for the Patient
with Periodontal Disease. Ont Dentist. Nov Issue. 32-39.
Pericoronitis
Spontaneous pain
Worse on biting
Signs of inflammation of the operculum
Trismus
Fever
lymphadenopathy
Cellulitis
Swelling
Tenderness
Erythema of the affected part of the face
Lymphadenopathy
Can be very serious
Cellulitis Abscess
Acute
Severe/generalized
Large
Diffuse borders
Greater degree of
seriousness
Chronic
Localized
Small
Well circumscribed
Less degree of seriousness
What is an antibiotic? An antibiotic is an imprecisely applied term,
generally used to describe any compound
(natural or synthetic) that inhibits the growth
of, or actively kills, microorganisms.
The Discovery of
ATB
“The Doctor” by Sir Luke Fildes
It was an accident
A. Fleming accidentally contaminated a plate with
a fungus
He observed a clearly defined region with no
bacterial growth where the fungi had contaminated
the plate.
The area around the fungus was eventually
referred to as a zone of inhibition.
Dr. Fleming
Fleming was not very knowledgble about fungi but he knew
that the mold in his dish was a species of penicillin
Later, it was determined to be Penicillum notatum
In 1929, Fleming published a paper detailing his discovery,
but it wasn’t until 10 years later that other scientists began
trying to use penicillin to treat clinical disease.
Dr. Florey and Dr. Chain
Florey experimented penicillin with mice and lethal doses of
streptococci.
Eight mice were injected with the bacteria and only four mice
received penicillin prior to the injection
The four that received penicillin survived and the others all
died.
Than later in 1941, they administer penicillin in human.
Worked to mass produce penicillin.
1945--- all three received Nobel Prize in Medicine.
For the first time, doctors had a way to treat infections and
miraculously save lives
Prior to the discovery of penicillin patients often died from
trivial injuries or infections
Today in the United States, deaths by infectious bacterial
diseases are one-twentieth what they were in 1900
It is estimated that over 80 million prescriptions are
written in North America each year.
12,500 tons of antibiotics are produced annually.
From 1900 to 1980, mortality from infectious
diseases dropped from 797 per 100,000 persons
to 36 per 100,000 persons.
SOME
DEFINITIONS
Types of Bacteria:
Aerobic Bacteria: Needs Oxygen to survive
Anaerobic Bacteria: Survives in the absence
of oxygen
BACTERIAL SHAPE:
(a) Round cocci
(b) Rod-like bacilli
(c) Spiral-shaped spirochetes
Gram Staining
- A test, resulting in the classification of
bacteria, developed in the last century by
Hans Christian Gram, a Danish
microbiologist
- Gram positive bacteria will retain the
original blue stain
- Gram negative bacteria will lose the blue
stain upon intermediate acetone treatment
and will stain red
Gram Staining Gram staining classification is based on ability of
the bacterial membrane to stain either red or blue
Bacteria that take up the red stain are classified as
gram positive, Gm(+)
Bacteria that take up the blue stain are classified
as gram negative, Gm(-)
Bactericidal: Kills the bacteria
Bacteriostatic: inhibits the growth of susceptible
bacteria, rather than killing them immediately; will
eventually lead to bacterial death.
.
Antibiotics with a bactericidal mode of action are preferred,
especially for treatment of immunocompromised patients.
The mode (static vs. cidal) of antibiotic action may differ for
different pathogens and may depend on the drug
concentration.
`
General Guidelines
Remove the cause of the infection is the
most important of all
I & D
Med Hx
Antibiotics are really an adjunctive therapy
Evaluate the patient carefully:
Severity of Infection
Patients host defenses
Treating the infection surgically (I&D)
Treating with antibiotics
Culture and Sensitivity Serious infections (life threatening)
Infections that persist or recur in spite of treatment
Previous multiple antibiotic treatment
Immunocompromised patients
Osteomyelitis
The ideal antibiotic:
1. Rapid onset of action
2. Specific for the pathogen
3. Does not disturb non-pathogens
4. No other side effects
5. Inexpensive
Antibiotic Misuse Use of antibiotic to treat a viral infection
Inadequate frequency
Inadequate duration
Overuse of broad spectrum antibiotics
Sub optimal dosage
Poor compliance with therapy
Retaining unfinished antibiotic for later use
Basic Principals Hit hard, fast and early.
Use the right drug.
Use the right dose.
Use the correct dosing schedule.
Use for the correct duration.
Classes of Antibiotics
Mechanism of Action
Spectrum of Activity/Therapeutic Uses
Mechanisms of Resistance
Doses
Adverse Effects
DIs
Mechanism of Action of
Antimicrobial
Inhibition of Bacterial cell wall synthesis
Inhibition of protein synthesis
Inhibition of nucleic acid synthesis
Inhibition of folic acid synthesis
Inhibition of Bacterial cell wall synthesis
Inhibition of protein synthesis
Inhibition of nucleic acid synthesis
Inhibition of folic acid synthesis
B-Lactam Antibiotics
Penicillin
Cephalosporins
Carbapenems
Monobactams
Vancomycin
PENICILLINS Bactericidal
All contain the Beta lactam ring
Binds to transpeptidase enzyme
Penicillin inhibits the transpeptidase enzyme which is
required to form cross links in the cell wall.
These transpeptidase are protein in the cell wall called
penicillin binding proteins.
The bacterial cell wall is a cross linked polymer called
peptidoglycan which allows a bacteria to maintain its shape
despite the internal pressure caused by osmotic pressure
differences.
If the peptidoglycan fails to crosslink the cell wall will lose its
strength which results in cell lysis.
All β-lactams disrupt the synthesis of the bacterial cell wall by
interfering with the transpeptidase which catalyzes the cross
linking process.
Mechanism of Resistance Bacteria produce enzymes that are capable of destroying
penicillins
B- lactamases
Most commonly produced by Gram –ve bacteria
Intrinsic defenses such as efflux pumps can remove the β-
lactams from the cell. β-Lactamases are enzymes which
hydrolyze the amide bond of the β-lactam ring, rendering the
drug useless.
Chemicals have been developed to inhibit these enzymes:
1. clavulanic acid
2. tazobactam
3. Sulbactam
These chemicals bind with beta-lactamase and prevent the enzyme from breaking down the penicillin
Penicillin-beta-lactamase inhibitor combination
drugs:
ampicillin + sulbactam = Unasyn
amoxicillin + clavulanic acid = Augmentin
ticarcillin + clavulanic acid = Timentin
piperacillin + tazobactam = Zosyn
Spectrum of Activity Penicillin G (IV) and Penicillin V (oral):
non-B-lactamase producing aerobic bacteria
oral anaerobes
Ampicillin (IV) & Amoxicillin (oral) have an added amino
group:
additional bacteria including gram positive enterococcus and
listeria, gram negative bacilli such as E. coli, B-lactamase
negative H. influenzae
Penicillin is the first choice for odontogenic infections
G (+) cocci and rods, spirochetes and anaerobes
ADRs As mammalian cells do not have a cell wall the
toxicity profile is very low
Allergic reactions (said to occur in 10-12 % of the
population)
Anaphylaxis reactions
Rashes
N &V
Diarrhea
Other ADRs
Seizures with high blood concentrations
C. difficile Pseudomembranous Colitis
(PMC)
Doses
Pen VK 300 mg QID (7-10 days)
Amoxil 500 mg TID (7-10 days)
Augmentin { Amoxil 500 mg & Clavulanate 125 mg}
BID
CEPHALOSPORINS
Bactericidal
Contain the B-lactam ring
Similar site of action (inhibit the transpeptidase enzyme)
Bacterial resistance
Classifications from 1st to 4th
SPECTRUM OF ACTIVITY
Cephalosporins are classified into four generations based on their activity.
Later generations generally become more effective against Gram (-) bacteria due to an increasing number of polar groups.
Ceftazidime (3rd gen) in particular can cross blood brain barrier and is used to treat meningitis.
Later generations are often the broadest spectrum and are reserved against penicillin resistant infections to prevent the spread of cephalosporin resistant bacteria.
1st generation: Cephalexin (250-500mg po q6h)
and Cefazolin IV
Skin and soft tissue, dental infections
Active against some gram positives, S.aureus, streptococcus
Some gram negatives E.coli, Klebsiella, Proteus and oral
anaerobes
2nd generation: Cefuroxime IV, Cefuroxime
axetil (250-500mg po q12h) and Cefaclor (250-
500mg po q8h)
Respiratory tract infections, otitis media
Gram positive coverage, expanded gram negative coverage,
oral anaerobes
3rd generation: ceftriaxone and cefotaxime (IV)
Greater gram negative coverage
Less active against gram positive bacteria
3rd generation: Ceftazidime (IV)
Expanded gram negative coverage including Pseudomonas
Reduced gram positive
4th generation: cefepime (IV or IM)
Gram negative organisms including Pseudomonas
Increased gram positive coverage
ADRs
Similar to Penicillns
Cephalosporins should be avoided in individuals
who are allergic to penicillins (about 8-12 % show
cross-reactivity)
Very little DIs.
CARBAPENEMS
Carbapenems are a potent class of β-lactams which attack a
wide range of PBPs.
have low toxicity.
much more resistant to β-lactamases than the penicillins or
cephalosporins.
Imipenem and Meropenem
Activity against gram positive, gram negative and anaerobes
Used in life threatening situations.
Cross reactivity with Penicillin (10-12 %)
Seizures are common with high doses of Imipenem
Vancomycin
Tricyclic glycopeptide
Bactericidal
Prevents growth of peptidoglycan polymer
Active against gram positive aerobic bacteria
Used IV for staph., strep., enterococcal infections resistant to penicillins
Mainly reserved for resistant infections
ADRs of IV use:
1. Fever, flushing and chills
2. Renal toxicity
3. Ototoxicity
4. Allergic reaction
Inhibition of Bacterial cell wall synthesis
Inhibition of protein synthesis
Inhibition of nucleic acid synthesis
Inhibition of folic acid synthesis
1. Aminoglycosides
2. Tetracyclines
3. Clindamycin
4. Macrolides
1. Single strand copy of DNA
2. RNA modify to mRNA
3. mRNA travels out of the nucleus
4. Ribosomes make proteins based on mRNA
5. Ribosomes differ between bacteria and humans
A number of antibiotics exert their antimicrobial
effects by targeting the bacterial ribosome.
Bacterial ribosome is smaller (70s) than
mammalian ribosome (80s) and is composed of
50s and 30s subunits
Inhibit either the 30s or 50s ribosomal subunit
(bacterial ribosomal subunits differ from
mammalian ones---drugs are selective for bacterial
protein synthesis)
AMINOGLYCOSIDES
gentamicin (Garamycin)
kanamycin
neomycin
streptomycin
tobramycin
amikacin (Amikin)
netilmicin
Susceptible organisms allow aminoglycosides to diffuse
through porin channels in their outer membranes.
These organisms also have an oxygen dependent
system that transports the drug across the cytoplasmic
membrane.
The antibiotic than binds the 30s ribosomal subunit and
inhibit translation of mRNA.
Uptake requires oxygen uptake mechanism, therefore
no activity against anaerobes.
Poor oral absorption (since they are highly polar;
no PO forms (except neomycin)
Very potent antibiotics with serious toxicities
Bactericidal
Kill mostly gram-negative; some
gram-positive also
Often used in combination with other antibiotics
for synergistic effect. e.g. B-lactams
ADRs
Cause serious toxicities:
Nephrotoxicity (renal failure)
Ototoxicity (auditory impairment and vestibular [eighth cranial
nerve])
Must monitor drug levels to prevent toxicities
Ototoxicity and nephrotoxicity are the most significant
BUT:
Headache
Neuromuscular blockade
Dizziness
Vertigo
Skin rash
Fever
Allergic reaction
TETRACYCLINES
demeclocycline (Declomycin)
oxytetracycline
tetracycline
doxycycline (Doryx, Doxy-Caps, Vibramycin)
minocycline
Mechanism of Action: Entry of these agents is mediated both by passive
diffusion and by an energy-dependent transport protein mechanism unique to the bacterial inner cytoplasmic membrane.
The drug binds reversibly to the 30S subunit of the bacterial ribosome, thereby blocking access of the amino acyl-tRNA to the mRNA-ribosome complex at the acceptor site
Thus, bacterial protein synthesis is inhibited.
Bacteriostatic—inhibit bacterial growth
Bind to Ca2+ and Mg2+ and Al3+ ions to
form insoluble complexes
Thus, dairy products, antacids, and iron
salts reduce absorption of tetracyclines
USES:
Wide spectrum:
gram-negative, gram-positive,
protozoa, Mycoplasma, Rickettsia,
Chlamydia, syphilis, Lyme disease.
Also effective for: Acne
Chronic bronchitis
Lyme disease
Mycoplasma pneumonia infection
Rickettsia infection
Some venereal diseases, such as Chlamydia infection
Traveler’s diarrhea
What about dental or Perio
Infection
To treat periodontal infections due to Aa:
Doxycycline 100mg qd x21 days
Tetracycline 250mg po q6h x 21 days
Minocycline 100mg po bid x 21 days
Aa (& other oral bugs) growing resistance----
Amoxicillin & metronidazole combination
Low dose doxycycline 20mg (Periostat®)
Side Effects and ADRs
1. Gastric discomfort
2. Super infection (overgrowth of no susceptible
organisms such as Candida)
3. Diarrhea
4. Pseudomembranous colitis
Strong affinity for calcium:
Discoloration of permanent
teeth and tooth
enamel in fetuses and
children
May retard fetal skeletal
development if taken
during pregnancy
Tetracycline Staining
Clindamycin
Mechanism of Action:
Binds irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting the translocation steps of protein synthesis
Bacteriostatic
Effective against:
1. Gram positives
2. anaerobes
3. Several oral pathogens
Skin and soft tissue infections such as
diabetic skin ulcer infections
Oral infections
Aspiration pneumonia
Side effects and ADRS:
Skin rushes
Diarrhea
Hepatotoxicity (rare)
Often implicated as cause of PMC
Treatment of PMC Stop all antibiotics
Keep the patient hydrated
Refer to a physician
Prescribe:
Vancomycin 500 mg po qid for 2 days (if severe)
Vancomycin 125 mg po qid for 10-14 days
Metronidazole 500 mg po tid for 7-14 days
MACROLIDES
Erythromycin was the first of these drugs (particularly if pt had allergy to the b-lactam antibiotics)
Erythromycin is a naturally-occurring macrolide derived from Streptomyces erythreus – problems :narrow spectrum, poor GI intolerance, short elimination half-life
Structural derivatives include clarithromycin and azithromycin:
Broader spectrum of activity
Improved PK properties – better bioavailability, better tissue penetration, prolonged half-lives
Improved tolerability
Mechanism of Action Inhibits protein synthesis by reversibly binding to
the 50S ribosomal subunit
Suppression of RNA-dependent protein synthesis
Macrolides typically display bacteriostatic activity,
but may be bactericidal when present at high
concentrations.
Gram positive aerobes (Staph. Aureus)
Respiratory pathogens including atypical bacteria
(S.pneumonia, M.pneumoniae, C.pneumoniae, legionella)
Clarithromycin and azithromycin more effective against some
gram negatives (H.influenzae, Moraxella, N.gonorrhoeae)
Otitis media, skin and soft tissue infections
Azithromycin – some activity against oral anaerobes
Dosage: Erythromycin IV, Oral 250mg qid (7-10 days)
Clarithromycin 250-500mg po bid (7-10 days)
Azithromycin IV, or oral 500mg stat then 250mg qd
for 4 days
ADRs Gastrointestinal :Nausea, vomiting, diarrhea,
dyspepsia
Cholestatic hepatitis - rare
ototoxicity (high dose erythro)
Allergy
Drug Interactions
Erythromycin and Clarithromycin – are inhibitors of cytochrome p450 system in the liver; may increase concentrations of:
Theophylline Digoxin
Carbamazepine Valproic acid
Cyclosporine Terfenadine, Astemizole
Phenytoin
Warfarin
Inhibition of Bacterial cell wall synthesis
Inhibition of protein synthesis
Inhibition of nucleic acid synthesis
Inhibition of folic acid synthesis
Quinolones Ciprofloxacin
Levofloxacin
Norfloxacin
Moxifloxacin
Mechanism of Action: • These agents enter the bacterium by passive diffusion
through water-filled protein channels (porins) in the outer
membrane
• Once inside the cell, they inhibit the replication of bacterial
DNA by interfering with the action of DNA gyrase.
• Binding of these agents to both the enzyme and the DNA
forms a complex that inhibit the resealing step, and can
cause cell death.
Bactericidal
Effective against gram-negative organisms and some gram-
positive organisms
Therapeutic Uses: 1. Lower respiratory tract infections
2. Bone and joint infections
3. Infectious diarrhea
4. Urinary tract infections
5. Skin infections
6. Sexually transmitted diseases
7. Dental Infections
Prototype: Ciprofloxacin-- Dose: IV,
oral 250-500mg po bid
IV, oral Levofloxacin 250-500mg qd
Moxifloxacin 400mg qd
ADRs: Mainly GI
Headaches, dizziness, blurred vision
Skin rushes
Seizures
Absorption reduced by cations
METRONIDAZOLE
Bactericidal
Effective against Bacteroides species, esp.
in periodontal infections
IV, oral dose: 250-500mg bid to tid
FDA category B (However, small number of
reports raised suspicion of teratogenic
effect)---USE CAUTIOUSLY
Metronidazole and the lactating mother
The use of metronidazole during lactation is
controversial
Excreted into breast milk in relatively high amounts
Concern expressed of adverse effects in nursing
infants
THM: USE CAUTIOUSLY
PK
Oral absorption is 80-85%
Metabolized in the liver
Half life is 8 hrs
Therapeutic Uses Anaerobic infections
Vaginal infections
Used with other antibiotics for H.pylori
Other protozoal infections
ANUG, oral abscesses
ADR
• GI (N&V, abdominal cramps)
• An unpleasant Metallic taste
• Dizziness and vertigo
What about alcohol and Metronidazole?
• Disulfiram-like reactions
• Metronidazole contain a moiety that is structurally related to disulfiram and may inhibit aldehyde dehydrogenase, thereby leading to accumulation of acetaldehyde
• Tell your pt to avoid alcohol while taking these medications and for 2-3 days after discounting the drug
Inhibition of Bacterial cell wall synthesis
Inhibition of protein synthesis
Inhibition of nucleic acid synthesis
Inhibition of folic acid synthesis
How does this works? • Enzymes requiring folate-derived cofactors are essential for the
synthesis of purines and pyrimidines (precursors of RNA and DNA) and other compounds necessary for cellular growth and replication
• Therefore, in the absence of folate, cells cannot grow or divide
• The sulfonamides (sulfa drugs) are a family of antibiotics that inhibit the synthesis of folate.
• Trimethoprim, a second type of folate antagonist, prevents microorganisms from converting dihydrofolic acid to tetrahydrofolic acid.
SULFONAMIDES They inhibit nucleic acid replication by interfering with the
synthesis of folic acid from PABA.
As indicated, folic acid functions as a coenzyme for transfer
of methyl group in nucleosides production
PABA---X--- Folic Acid-------DNA Synthesis
Mode of action –
These antimicrobials are analogues of para-aminobenzoic acid
and competitively inhibit formation of dihydropteroic acid.
Bacteriostatic
Used in combination with Trimethoprim
Broad range activity against gram-positive
and gram-negative bacteria; used primarily
in urinary tract and Nocardia infections.
Oral absorption is excellent 95%
Half life is 9-10 hrs
ADR
Crystalluria
Hypersensitivity
Hemolytic Anemia
Hepatitis
TRIMETHOPRIM
Bacteriostatic
Mode of action - These
antimicrobials binds to
dihydrofolate
reductase and inhibit
formation of
tetrahydrofolic acid.
TRIMETHOPRIM
Spectrum of activity - Broad range activity against
gram-positive and gram-negative bacteria; used
primarily in urinary tract and Myocardia infections.
Resistance - Common
Combination therapy - These antimicrobials are used in
combination with the sulfonamides; this combination
blocks two distinct steps in folic acid metabolism and
prevents the emergence of resistant strains.
ANTIVIRAL AGENTS
Viruses are obligate intracellular parasites
They lack both a cell wall and a cell
membrane
They do not carry metabolic processes
Viral reproduction is done by the host’s
metabolic machinery (drugs can affect the
host)
Viruses consist of a small collection of
genetic material (DNA or RNA) encased in
a protective protein coat that is called
capsid.
Some viruses have an additional layer
around this coat that is called envelope.
Therapy is further complicated by the fact
that clinical symptoms appear late
At this time, drugs that block viral
replication has limited effectiveness.
Some antiviral are good and useful as
prophylactic agents
Steps: 1. Virus attachment and entry
2. Uncoating of virion
3. Migration of genome nucleic acid to the nucleus
4. Transcription
5. Genome replication
6. Translation of virus mRNA
7. Virion assembly
OROLABIAL HERPETIC
INFECTIONS
Represent the most common viral infection.
Herpes Viruses are a leading cause of human viral
diseases, second only to influenza and cold
viruses.
Are capable of causing overt disease or remaining
silent for many years only to be reactivated.
Name Herpes comes from the Latin herpes which,
in turn, comes from the Greek word herpein which
means to creep.
Herpes Simplex Virus (HSV)
These are very large viruses and their
genome encodes at least 80 proteins.
Half are not directly involved in the virus
structure.
Almost any human cell type can be affected
by HSV.
HSV-1 and HSV-2
Transmitted via direct contact with contaminated secretions from an infected individual
Incubation period of 2-20 days
HSV-1 is predominantly associated with orolabial disease
HSV-2 is predominantly associated with genital disease
Asymptomatic or mild.
Acyclovir Chemistry:
Acyclovir, gancyclovir, famcyclovir, pemcyclovir all are
guanine nucleoside analogs.
Acyclovir Mechanism of action All drugs are phosphorylated by a viral thymidine-kinase,
then metabolized by host cell kinases to nucleotide analogs.
The analog inhibits viral DNA-polymerase
Only actively replicating viruses are inhibited
Antiviral spectrum Acyclovir: HSV-1 (Herpes simplex virus), HSV-2, VZV
(Varicella Zoster virus)
Gancyclovir: HSV-1, HSV-2, VZV, EBV , CMV (cytomegalovirus).
Acyclovir
Therapeutic uses Acyclovir is the drug of choice for:
Genital HSV infections
HSV encephalitis
Cold sores HSV
Oral Herpes Simplex:
Acyclovir 400mg TID
Valacyclovir 1000mg BID
Famciclovir 250mg TID
Adverse effects
Nausea and vomiting ,diarrhea
Neurotoxicity (1-5% of patients) (headache, tremor,
behavioral changes, delirium, seizures, coma)
Nephrotoxicity (high doses)
neutropenia, thrombocytopenia (gancyclovir)
ANTI-FUNGAL AGENTS
Infectious diseases caused by fungi are called mycoses
Some infections are superficial some involve the skin
Some fungi may penetrate the skin, causing subcutaneous
infections
May be dangerous
Fungi have rigid cell well composed of chitin (a polymer of N-
acetyl glucosamine)
The cell membrane contains ergosterol (this is good…… )
1. Superficial : Affect skin – mucous membrane:
(e.g.)
Dermatophytes : Fungi that affect keratin layer of
skin, hair, nail. e.g. tinea pedis ,ring worm infection
Candidiasis : Yeast-like, oral thrush, vulvo-
vaginitis.
2. Deep Infections: e.g.
Affect internal organs as : lung ,heart, brain leading
to pneumonia , endocarditis , meningitis.
FUNGAL
INFECTIONS IN THE
ORAL CAVITY
Candidiasis The outcome of an overgrowth of Candida albicans
Due to:
Antibiotics
Cancer chemotherapy
Corticosteroid therapy
Dentures
Diabetes mellitus
HIV infection
xerostomia
156
Types Pseudomembranous candidiasis
Erythematous candidiasis
Denture stomatitis
Chronic hyperplastic candidiasis
Angular cheilitis
Chronic mucocutaneous candidiasis
Median rhomboid glossitis
157
Pseudomembranous candidiasis
A white curdlike material is present on the mucosal surface.
The mucosa is erythematous underneath.
The patient may complain of a burning sensation and/or a metallic taste.
Epstein et al., 2001
Erythematous candidiasis
The presenting complaint is an
erythematous, often painful
mucosa.
May be localized to one area of
oral mucosa or be more
generalized
Erythematous candidiasis 161
Epstein et al., 2001
Denture stomatitis
The most common type of candidiasis
The mucosa is erythematous, but the change is limited to the mucosa covered by a full or partial denture.
The pattern follows the outline of the RPD or denture.
Usually asymptomatic
163
Erythema or fissuring at the labial
commissures
Most commonly from Candida,
but may be caused by other
factors such as nutritional
deficiency
165
Angular cheilitis
Epstein et al., 2001
1. Amphotericin B
2. Nystatin
3. Azoles
Amphotericin B
A polyene molecule which is not water soluble
Binds to the ergosterol molecules in the membrane
of the fungus. This binding makes the membrane
dysfunctional and electrolyte imbalance occur.
It creates pores in the membrane , there is a leakage of
cations and that causes cell death.
Does not affect us human bc we have cholesterol…
PK • Poorly absorbed orally (very large molecule).
• IV
• Highly bound to plasma protein.
• Metabolized in liver.
• Excreted slowly in urine over a period of several days.
• Half-life 15 days.
Therapeutic Uses A broad spectrum activity
Kills most Candida
Kills most Aspergillosis (Yeast)
ADRs
Infusions related side effects (fever, aches, muscle
spasms, vomiting etc…)
Nephrotoxicity
DIs
Do not use with other drugs that may cause renal
toxicity
Nystatin • It is a polyene, similar in structure & mechanism to
amphotericin B.
• Used only topically.
• It is available as creams, ointment , suppositories & other
preparations.
5mL swish and swallow TID
ADRs- rare because of its lack of absorption orally.
(N&V may occur)
AZOLES
A group of synthetic fungistatic agents with a broad spectrum of activity.
They are classified into :
Imidazole group
Triazole group
MOA: Inhibit the fungal cytochrome P450 enzyme, (α-demethylase)
which is responsible for converting lanosterol to ergosterol
Significant drug interactions
`
Interactions that happen
through CYP enzymes are
either based on enzyme
induction or inhibition.
INDUCTION
Drug A induces the body to produce more of an enzyme which metabolized Drug B
This reduces the amount of drug B, which may lead to loss of drug B’s effectiveness
INHIBITION
Drug A inhibits the production of enzymes to metabolize Drug B
This increases the amount of Drug B in the body and could lead to an overdose or toxic effects
Imidazole
Ketoconazole
Miconazole
Clotrimazole
Ketoconazole
Used topically or systematic (oral route only ) to treat Oral &
vaginal candidiasis.
ADRs: Nausea, vomiting ,anorexia, Hepatotoxic, Menstrual
irregularities, Impotence
DIs:
CYP450 inhibitor
Can potentiate the toxicities of drugs such as cyclosporine,
phenytoin, triazolam, warfarin
Warfarin Warfarin + Inhibitor Ketoconazole
90% --- INR : 5.2
Increased Bleeding
Triazoles
Fluconazole
Itraconazole
Voriconazole
Fluconazole Same MOA as Ketoconazole
Water soluble
Completely absorbed from GI tract
PO or IV
Excellent bioavailability after oral administration
Clinical use: very effective against candidiasis
ADRs: less than Ketoconazole (N & V)
DIs: Inhibitor of the 3A4 and 2C9
Warfarin, phenytoin, cyclosporine, tacrolimus, rifampin/rifabutin, sulfonylureas
Summary:
• Ketoconazole rarely used
• Fluconazole (IV and oral)
– Candida infections and fungal meningitis
– Fungal vaginitis 150mg
– 100-200mg once daily for oral candidiasis
• Itraconazole (IV and oral)
– candida infections
DIs with anti-
infectives
Antibiotics with Oral Contraceptives (effectiveness is
decreased)
The interaction between Antibiotics and OC: Estrogens are metabolized (liver) into active metabolites or conjugated
metabolites
Metabolites are mostly excreted through bile into the intestine (insoluble)
BUT, normal GI flora helps hydrolyze the conjugated metabolites into active, reabsorbable compounds
They return to blood stream
THIS IS ‘ENTEROHEPATIC CIRCULATION’ phenomenon
Therefore:
normal GI flora increases enterohepatic cycling of estrogens
Antibiotics that interfere with this flora may reduce the blood levels of estrogens and decrease the efficacy of oral contraceptives
Macrolides(erythromycin, clarithromycin,
azithromycin)
1. Anticoagulants--- Risk of bleeding disorders increased.
2. Clindamycin-- Possible antagonism, avoid concurrent use.
3. Digoxin--Increased digoxin levels in 10% patients. Use with
caution (avoid, if possible in elderly).
4. Midazolam,triazolam--- Increased benzodiazepine levels,
use concurrent combination with caution.
Metronidazole 1. Anticoagulants-- Risk of bleeding disorders increased.
Consult with physician.
2. Ethanol Can result in: dizziness,flushing,nausea. Avoid
3. Lithium--Increased lithium levels, possible toxicity, consult
physician.
4. Phenytoin--0 Effect of phenytoin may be increased, monitor
closely.
Antibiotics during
pregnancy and
lactation
FDA Classification System
A: No risk to the fetus
B: No risk to the fetus But there are no adequate and well-
controlled studies in pregnant women
C: Adverse effect on the fetus on animals, but there are no
adequate and well-controlled studies in humans.
Consider Potential benefits v. potential risks
D: Positive evidence of human fetal risk based on adverse
reaction data from investigational or marketing experience
or studies in humans.
Consider Potential benefits v. potential risks
X: Studies in humans or animals have demonstrated fetal
abnormalities and/or there is positive evidence of human
fetal risk based on adverse reaction data from
investigational or marketing experience, and the risks
involved in use of the agent in pregnant women clearly
outweigh the potential benefits.
Penicillin
FDA--- B
• Safe in all trimesters
• No teratogenic
• Amoxicillin and cephalosporins also considered safe to use during pregnancy
• Amoxicillin and cephalosporins also considered safe to use during breastfeeding
• No increase risk of malformations with amoxicillin-clavulanic acid (Clavulin) in several studies (Br J Clin Pharmacol 2004 and Eur J Obstet Gynecol Reprod Biol 2001)
Erythromycin
FDA Category B
Do not use the estolate form because it may cause
cholestatic hepatitis
Tetracycline Usually not the drug of choice for oro-facial
infections
May be used for periodontal infections
FDA Category D
Tetracycline or doxycycline whether administered systemically or subgingivally are CONTRAINDICATION DURING PREGNANCY
Metronidazole Used for periodontal conditions
FDA category B
Small number of reports raised suspicion of teratogenic effect
USE CAUTIOUSLY
Metronidazole and the Lactating
mother The use of metronidazole during lactation is controversial
Excreted into breast milk in relatively high amounts
Concern expressed of adverse effects in nursing infants
THM: USE CAUTIOUSLY
Other Antibiotics which we may
use Clindamycin (FDA category B)
Azithromycin (FDA category B)
What about Chlorhexidine rinse? FDA Category B
SAFE TO USE FOR PREGNANAT WOMEN
SAFE TO USE FOR Lactating mother
Antifungals Nystatin- FDA Category B
Ketoconazole- FDA Category C (use cautiously)
Fluconazole- FDA Category C (use cautiously)
Antibiotics in Pregnancy
FDA Category Antibiotics in Category
A
B Penicillins, Cephalosporins, Carbapenems (except Imipenem),
Daptomycin, Vancomycin (oral), Clindamycin, Erythromycin,
Azithromycin, Metronidazole (avoid first trimester),
Nitrofurantoin, Acyclovir, Amphoterocin B, Ethambutol
C Quinolones, Chloramphenicol, Clarithromycin, Imipenem,
Linezolid, Trimethoprim/Sulfa (D if used near term),
Vancomycin (IV), Rifampin, INH, PZA, PAS, Fluconazole,
Caspofungin
D Tetracyclines (Doxy, Tige, Mino), Voriconazole,
Aminoglycosides (some put gentamicin as a category C)
X Ribavarin
Antibiotics during pregnancy
Geriatric
Patients
There are no specific changes in the
therapeutic use and dose of anti-infectives in
our elderly healthy pts.
However, doses may need to be reduced
because of decreased lean body mass,
especially older women
ADRs
Also, there are number of potential drug
interactions that may lead to modification of
the anti-infective that we select.
Examples
Cephalothin can cause nephrotoxicity at high doses
Erythromycin can cause ototoxicity if impaired renal function is
present.
Clindamycin can increase the incidence of GI problems such as
diarrhea and colitis.
Clarithromycin (and Clindamycin) may interact with
digoxin (this Anti-infective may decreases the
clearance of digoxin from the body)
Metronidazole and Ciprofloxacin will increase the
anticoagulant effect of Warfarin by decreasing its
hepatic metabolism.
Table 4: Antimicrobial-induced adverse drug reactions in elderly patients.
Antibiotic Adverse drug reaction
Beta-lactam antibiotics
Diarrhea, drug fever, interstitial nephritis,
thrombocytopenia, Clostridium difficile-
associated colitis, rash, anemia, neutropenia
Clindamycin Diarrhea and Clostridium difficile-associated
colitis
Erythromycin, clarithromycin Cholestatic hepatitis, Clostridium difficile-
associated colitis
Azithromycin QT prolongation, ototoxicity
Fluoroquinolones Nausea, vomiting, QT prolongation
Tetracyclines Photosensitivity
Doxycyclines Esophageal ulcers
Sources: Becker (2014),34 Kee (2012)51 and Faulkner et al. (2005).53
From: “Pharmacotherapy for the Elderly
Dental Patient”
Ouanounou, A and Haas, D. JCDA. 2015
Table 5: Antimicrobial-induced drug interactions in elderly patients.
Antibiotic Interacting drug Effect
Amoxicillin Allopurinol Rash
Fluoroquinolones
Pharmaceuticals containing
aluminium, magnesium, iron
or zinc
↓ absorption of
fluoroquinolones
Antiarrhythmic Ventricular arrhythmia
Metronidazole
Warfarin ↑ effect of warfarin (monitor
INR)
Alcohol Disulfiram-like reaction
Phenytoin ↑ phenytoin levels
Azithromycin Pharmaceuticals containing
aluminium or magnesium
↓ absorption of
azithromycin
Clarithromycin and
erythromycin
HMG-CoA reductase
inhibitors, cyclosporine,
digoxin, warfarin,
theophylline
↑ effect of interacting drug
Tetracyclines
Pharmaceuticals containing
aluminium calcium,
magnesium, iron and
antacids
↓ absorption of
tetracyclines
Digoxin ↑ digoxin levels and risk of
toxicity
Source: Faulkner et al. (2005).53
ANTIBIOTIC
PROPHYLAXIS
What is Infective endocarditis (IE) Is an infection of the lining of heart chambers or valves with bacteria,
fungi, or other organisms.
IE occurs most commonly in people who have abnormal heart valves or had previous heart surgery; less commonly, it can occur in otherwise healthy people who have do not have heart disease
Infective endocarditis develops following a sequence of events:
Bacteria circulate in the bloodstream and stick to the lining or valves of the heart, usually at a site of previous injury or surface irregularity or abnormality.
The bacteria then grow on the valve surface, forming a small mass (called a vegetation) on the heart valves or lining. The valve or surface that is infected may then become secondarily damaged.
Why did the guidelines changed IE is much more likely to result from frequent exposure to
random bacteremias associated with daily activities
Prophylaxis may prevent an exceedingly small number of cases of IE, if any
The risk of antibiotic-associated adverse events exceed the benefit, if any, from prophylactic antibiotic therapy
Maintenance of optimal health and hygiene may reduce the incidence of bacteremia and is more important than prophylactic antibiotics for a dental procedure to reduce the risk of IE
Indicated for Pts with: Prosthetic heart valves
History of infective endocarditis
Cardiac transplant with subsequent heart valve problem
Some congenital heart conditions
Repair heart defects
ATB Pro not indicated for patients with: Surgically constructed systemic pulmonary shunts
Previous coronary artery bypass graft surgery
Physiologic (functional, innocent) heart murmurs
Pacemakers and implanted defibrillators
What procedures:
Implant placement, perio surg, exos, endo
beyond the apex, placement of orthodontic
bands, SRP etc…
Doses 1 hr prior to the appt:
Amoxicillin 2 g OR Peado: 50 mg/kg
Clindamycin 600 mg OR Peado: 20 mg/kg
Azithromycin 500 mg OR Peado: 15 mg/kg
Clarithromycin 500 mg OR Peado: 15 mg/kg
What about Total Joint Prosthesis
Controversial
Literature is not clear
The CDA recommended that `routine antibiotic
prophylaxis is NOT indicated for dental patients
with total joint replacements, nor for patients with
orthopedic pins, plates and screws`` (CDA position
: Dental patients with total joint replacement:
Approved November 2007, revised June 2013)
May be indicated for patients at increased risk including:
< 2 years post-surgery
Immunosuppression (incl. drug-induced, radiation-induced, HIV)
Previous joint infections
IDDM
Consult with the Orthopedic Surgeon
Amoxicillin or cephalexin 2 g po, 1 hour pre-op
OR
Clindamycin 600 mg po, 1 hour pre-op
Summary
Medical Hx
Dental Hx
Determine the etiology
Diagnosis
Rx
Rx only when there is an indication
Choose the narrowest spectrum drug that will be
effective
Consider the risks/benefits
Prescribe an adequate dose (freq and duration)
If your therapy is successful ----- good
If your therapy is failing Why? (Wrong drug,
bacterial resistance, host problems, pt compliance)
THANK YOU!