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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

[email protected]

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

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

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

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

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


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

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!

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