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ANTIBIOTICS IN ORAL AND MAXILLOFACIAL
SURGERY.
- Dr Sagar Jangam
HISTORY OF ANTIBIOTICS.
Sir William osler once said *The desire to take medicine is perhaps the
greatest feature which distinguishes man from animals *
1550 BC – The writings of ebers papyrus described more than 700
prescriptions.
Even in folk medicine drugs like opium (morphine), belladona (atropine),
cinchona bark (quinine) etc have been used even in those days.
1877 – Louis pasteur demonstrated coined the word *Antibiosis*
1890-1935 – Ehrlich suggested that dyes may be toxic to pathogenic
microorganisms.
1929 – Paul ehilich and Alexander fleming who were doing research in
vaccination discovered penicillin accidently.
and by 1941 penicillin was available commercially.
ANTIMICROBIAL DRUGS.
• Drugs in this class are designed to inhibit, kill the infecting organisms and
to have no/minimal effect on the recipient.
The therapy using these drugs is called chemotherapy
meaning *Treatment of systemic infections with specific drugs which
selectively suppress infected micro organisms, without significantly
affecting the host*
CLASSIFICATION
Based on type of organism primarily acting against:
• Antibacterial : penicillin,aminoglycosides etc
• Antifungal : griseofulvin,cotrimazole,amphotericinB
• Antiviral : acyclovir,ziduvidine
• Antiprotozoal: chloroquine,metronidazole
• Antihelmenthic: mebendazole,pyrentel
Based on spectrum of activity
Narrow spectrum : penecillin g ,streptomycin ,erythromycin
Broad spectrum : tetracycline and chloramphenicol
Extended spectrum: newer generation narrow spectrum
antibiotics like penecillins,cephelosporins and aminoglycosides.
Based on the type of action
• Bacteriostatic :
Sulfonamides
Tetracyclines
Erythromycin
Ethambutol
• Some static drugs may
become cidal at higher
concentrations.
•Bactericidal :
Penicillin
Aminoglycosides
Polypeptides
Rifampicin
Co trimoxozole
Cephelosporins
Vancomycin
Ciprofloxacin
• Some cidal drugs may
become static.
Based on the mechanism of action :
A. Inhibit cell wall synthesis :
Penicillin, vancomycin, cephelosporins
B. Leakage from cell membrane :
Polymyxin, bacitracin, amphoteracin B
C. Inhibits protein synthesis :
Tetracyclines, chloramphenicol,erythromycin
D. Misreading of m RNA and affects membrane permeability :
Aminogylcosides
E. Inhibits DNA gyrase :
Flouroquinolones,ciprofloxacin
F. Interfers with DNA function :
Rifampicin, metronidazole
G. Interferes with the DNA synthesis :
Acyclovir , zidovudine
H. Interferees with the intermediary metabolism :
sulfonamides, trimetoprim, ethambutol
PENICILLIN
• First antibiotic to be used
• The molecule consists of fused thiazolide and beta lactam
rings with attached side chains.
• Highly water soluble and deterioates rapidly under room
temperatures. Hence it is dispensed in it’s stable powder
form. Can be kept stable in the liquid form at 4 deg c. for 3
days.
• The prototype penicillin was penicillin G.
• It’s limitations were: Acid instability, Narrow Spectrum,
Rapid renal excretion.
• Thus penicillin V, extended spectrum and penicillinase
resistant were developed.
Mechanism of action.
• R-C-NH-CH-CH C
O=C N COOH
O S
CH
CH
3
3
Region where penicillinase acts.
Various
derivatives
attached here
Interfere with synthesis of
bacterial cell wall.
Inhibition of transpeptidase
preventing cross linking of
peptidoglycans.
Link to penicillin binding
proteins found on the cell
membrane.
Cell wall deficient bacteria
multiply.
CWD bacteria swell and burst.
Gram positive organisms are
entirely peptidoglycan linked
and are thus susceptible.
Rapid cell wall synthesis
occurs during multiplication and
hence these agents are more
active during this phase.
Classification of penicillins
• Natural penicillins
• Penicillin G
• Procaine penicillin
• Fortified procaine penicillin
• Benzathine penicillin
• Beta lactam inhibitors:
• Clavulanic acid
• Sulbactam.
Semi synthetic penicilin.
1.Acid resistant :
penicillin v.
2.Penicillinase resistant:
Methicillin, Cloxacillin.
3.Extended Spectrum :
a.Aminopenicillin:ampicillin
amoxycillin.
b.Carboxypenicillin: Carbencillin,
Ticarcilin
c.Ureidopenicillin:
Piperacillin.
d.Mecillinam:
Common disease entities for which penicillins
are used in OMFS
• Abscess.
• Gram Positive Bacteraemia.
• Endocarditis.
• Mastoiditis.
• Oro dental infections.
• Osteomyelitiis.
• Vincent’s infection.
• Pharyngitis.
• Wound infections.
These diseases are caused by a variety of gram positive cocci and bacilli,
and a few gram negative organisms. So sensitivity testing is a must.
Allergic Reactions.
• 1 to 10% of the patients show allergic reactions.
• Topical application: most likely to cause sensitization- should not be
used.
• Life threatening fatalities likely to happen parentrally.
• Penicillin g associated with highest drug allergy.
• 0.02 % show anaphylaxis of which 5% die of cardiac and respiratory
embarrassment.
• Foods (milk, beef etc.) exposed to penicilin can sensitise people
inadvertently, as this antibiotic is used widely in agriculture.
• Thus it is imperative that the patient be tested each time before a
regimen.
Classification of allergic reactions:
• Acute allergic reaction : Anaphylactic shock.
• Occur within 30 minutes of administration.
• Accelerated allergic reaction :
• Occur 30min to 48 hrs after penicillin administration.
• Not life threatening, but laryngeal edema may cause respiratory
embarrassment.
• Delayed allergic reaction :
• Takes two or more days to develop.
• Most commonly ocuring( 80 to 90% of the cases in which penicillins are
used.)
Commercialy available penicillin
preparations
Penicillin G (oral) Pentids 2-8lac units 6-
12 hrs
Oral
Penicillin G Pfizerpen 10-24 lac units
24 hrs
i.v. or i.m.
Penicillin G
procaine
Crystacillin 0-6-4.8 lac units
24 hrs
i.m
Penicillin G
benzathine
penidure 0.6-2.4 lac units
24 hrs
i.M or i.v
Fortified
penicillin
Fortified pp 3 lac procaine+
1 lac pen G
i.M or i.v
Semi synthetic penicillins
Penicillin v Crystapen v 250-500 mgs
6hrs
oral
Cloxicillin klox 250-500mgs 6
hrs
Oral, i.m, i.v
Ampicillin Ampilin
,roscillin
500mgs-2 gms
6hrs
Oral, i.m, i.v
Amoxicillin novamox 250mg-1gm 6
hrs
oral
Carbenecilin carbellin 1-5 gms 6 hrs i.M , i.v
Pipericillin piperapen 1-2.5gms 6 hrs i.m, above 2
gm i.v
Beta lactamase inhibitors
• These drugs bind to the penicillanase enzyme rendering them inactive
against the beta lactam ring.
• The bond is irreversible and hence are called as suicide inhibitors
• Commercially available preparations are combines with penicillins
Commercially available preparations
Clavulanic acid Augmentin Amoxycillin-
250mgs
+clavulanic acid
-125 mgs 6 hrs
Oral,
Sulbactum sulbasam Ampicillin 1
gm+ sulbactum
500mgs 6 hrs
Deep i.m, i.v
Spectrum of activity of penicillins
• Naturally occurring penicillins and penicillin v
• Gram positive cocci and bacilli
• Also gram negative neisseira
• Sensitive to spirochetes
• Resistance to penicillanase producing organisms
• Extended spectrum penicillins
• All above mentioned organisms and gram negative organisms like H influenzae, E
coli, Salmonella, shigella, Proteus
• Amoxycillin is better tolerated orally but not as potent as ampicilin
Penicillinase resistant penicillin
These drugs have side chains that protect them
from attack of penicillinases
Penicillin resistant staphylococcal infections.
It is not active against MRSA and VRSA.
Carboxy penicillin and urido penicillin(pipericillin)
They are active against pseudomonas and
klebsiella.
CEPHELOSPORINS
• It is also a beta lactam antibiotic
• These drugs bind to different protein in the cell membrane than that of
penicillins
• Another reason for limited cross sensitivity and a variation in the
spectrum amongst this family of drugs is that different molecules of
cephelosporins bind to different protein sites.
• There is 10% chance of cross resistance to penicillin.
• They are subdivided into four generations and the first are more active
against gram positive and the later are more active against gram
negative organisms.
Generations of cephelosporins
• First generation cephelosporins
Cefadroxil
Cephelexin
• Second generation cephelosporins
Cefuroxime
Cefaclor
• Third generation cephelosporin
Cefetaxime
Ceftriaxone
Ceftazidine
Cefoperazone
Cefixime
• Fourth generation cephelosporins
Cefepime
Cefpirome
Spectrum of activity of first generation
• Generally have the same spectrum as that of penicillins
• Some activity against klibsiella and e.coli
• Cefedroxil is a specific second line of drug used in bacterial endocarditis
Spectrum of activity of second generation
•Highly resistant to penicillinase producing
organisms
•Has better gram negative activity as compared to
the first generation
•It is also active against some anerobes
•It is thus used extensively in surgical infections of
mixed nature.
Spectrum of activity of third generation
•Excellent activity against gram negative organism
•Not so efficient against gram positive organisms
•Highly resistant against beta lactamases
•The newer drugs have a high activity against
pseudomonas (ceftazidime, cefoperazone)
Spectrum of activity of fourth generation
• They have better activity against some organisms resistant to older
generation cefelosporins
• They have superior action on pseudomonas and staphylococcus
Commercially available cephalosporins
Cephalexin spoidex 250-1gm 6hrs oral
Cefedroxil droxil 500mg-1gm
8hrs
oral
Cefuroxime cefogin 750mgs-1.5
8hrs
i.m, i.v
Cefeclor keflor 250mgs 8hrs oral
Cefotaxime Omnatax 1-2gms 8hrs i.m, i.v
Ceftriaxone monotax 1-2gms 24hrs i.m, i.v
Ceftadizime cefazid 500mgs-2gms
8hrs
i.m, i.v
Cefopirazone magnamicin 250mgs-2gms
8hrs
i.m, i.v
Cefexime orfix 250-400mgs
8hrs
oral
Cefipime kefage 1-2gms 8hrs i.v,i.m
Indications of cephalosporins
• Patients who show minor allergic reaction to penicillin,it can be used with
caution.
• Gram negative soft tissue infections and urinary tract infections
• Iatrogenic infections
• Penicillanase producing staphylococcal infections
• Surgical prophylaxis
• Other mixed infections
Aminoglycoside Antibiotics
•Aminoglycosides were drugs produced not by
chance like penicillin but were produced in a
deliberate search for products effective against
gram negative bacteria.
•Streptomycin was the first drug to be produced by
Waksman in 1944.
•All aminoglycosides are produced by soil
actinomycetes.
Important properties of aminoglycosides
• They are highly water soluble and are stable for months
• They are not absorbed orally and do not penetrate brain or csf.
• They are excreted in the urine in the unchanged form
• All are bacteriocidal and are more active in alkaline ph.
• They are active against gram negative bacilli.
• They have only partial cross resistance so an organism resistant to one
aminoglycosides may still respond to another.
• They have a very narrow margin of safety between therapeutic and toxic
concentrations.
• They all exhibit ototoicity and nephro toxicity.
Mechanism of action
• They are transported in two main steps :
A. Transport of the drug through the bacterial cell wall.
B. Binding to the ribosomes resulting in inhibition of protein
synthesis.
1.They diffuse through the outer coat of gram negative bacteria
through their porin channel
2.Entry to the cytoplasm is carrier mediated.
3.Entry is mediated by maintenance of polarized membrane and
is also oxygen dependent.
Thus penetration is dependent on the presence of oxygen and
so they are not active in big abscess. Also the penetration is
also favored by high ph(20 times more active in alkaline
medium than acid medium.)
4.Once inside streptomycin binds to the 30s ribosomes whereas
the others bind to 50s ribosomes and 30s-50s interface.
5.This causes the misreading of the mRNA codon.
But the cidal action of these antibiotics is mainly caused by the
changes caused in the bacterial cell membrane.
They incorporate defective proteins in the cell membrane which
causes the leak out of ions, aminoacids and even protein t
cause cell death.
The cidal action is concentration dependent and is related to the
peak concentration of the drug to the minimum inhibitory
concentration values.
Post antibiotic effect
This is after a brief exposure to the antibiotic if the
organism is placed in a antibiotic free medium it
starts multiplying again but after a lag phase. The
length of this lag phase depends both on the
antibiotic as well as the bacteria itself.
So it is argued that though the half life of
aminoglycosides is (2 – 4 hrs) a single injection of
the antibiotic is more effective and also less toxic
than 3 divided doses which are used conventionally.
Spectrum of activity of aminoglycosides
• Active against P aeruginosa, klebsiella, proteus
• Gentamycin is added to penicillin or a third generation cephelosporin in
treating serious infections.
• Tobramycins only use is in the treatment of serious proteus and
pseudomonas infections.
• Amikacin is used as a reserve drug for hospital acquired gram negative
bacilli infections and when resistance has developed to both gentamycin
and tobramycin.
Commercially available aminoglycosides
Sreptomycin Ambysterin-s 1gm 8 hrs
Above 50yrs(
0.75gms)
i.m
Gentamycin Garamycin 20- 240 mg /vial
calculated for
pt.
i.m, i.v
Tobramycin tobacin 3-5mg/kg in 1-3
divided
doses/day
i.v
Netilmicin netromycin 4-6mg/kg/day in
3 divided doses
i.v
Neomycin nebasulf Neomycin-5mg
Bacitracin-250u
Sulfacitamide-
60mg/gm
Surface
application
Newer drugs in aminoglycosides
•Gentamycin PMMA ( poly methylmethacrylate)
This is a new drug delivery system uded in
osteomylitis.
This consists of a small acrylic beads each impregnated with
7.5mg gentamycin sulphate and threaded over a surgical
grade wire. when this is placed after the removal of the
sequestrum for 10 days high cure rates have been achieved.
Dose regulation
• The dose must be presicely calculated
as it has a narrow margin of safety.
• Average adult dosage : 3 – 5mg/kg/day
i.m in a single dose
• The creatine clearance is also taken
into account.
• Normal adult creatine clearance :
about 100ml/min
• Loading dose need not be reduced (
unless edema is present) but the
maintanence dose has to be reduced.
• Cl clr(ml/min) Reduce
dose by
50-70 1.5times
30-50 2 times
10-30 3 times
05-10 6 times
Indications and interactions
• To be avoided during pregnancy as there is risk of fetal
ototoxicity
• Avoided with other ototoxic drugs like minocycline and high
ceiling diuretics.
• To be avoided with other nephrotoxic drugs like vancomycin,
amphoteracin B.
• Should be used cautiously in patients past middle age and
those who have kidney damage
• Aminoglycosides should not be mixed with any other drug in
the same syringe/infusion bottle.
Quinolones
• Entirely synthetic antimicrobials.
• Nalidixic acid was the first to be introduced in early 1960.
• In 1980s fluroquinolones were formulated .
• They had high potency, expanded spectrum ,slow
resistance development, better tissue penetration and
good tolerability.
Generations of flouroquinolones
•First generation :
• Norfloxacin
• Ofloxacin
• Ciprofloxacin
• Perfloxacin
•Second generation :
• Lomefloxacin
• Sparfloxacin
• Levofloxacin
• Gatifloxacin
• Moxifloxacin
Mechanism of action
• Inhibits enzyme DNA gyrase which nicks the double stranded DNA
introduces negative supercoils and then reseals the nicked ends.
• The DNA gyrase consists of two A and two B subunits.
• Under normal circumstances
Subunit A nicks the DNA.., Subunit B introduces the negative
supercoil..,Subunit A again reseals the DNA.
• This drug has a very high affinity to the Subunit A so it interferes with the
cutting and the resealing action thus faulting the bacterial replication.
Its bacteriocidal action is due to the digestion of the DNA by the
exonucleases whose production is signalled by the damaged DNA.
Spectrum of activity of fluroquinolones
• Highly susceptible organisms
E.coli Shigella
K.pneumonia H.influenzae
Enterobacter Proteus
Salmonella Yersinia enterocolitica
• Moderately susceptible organisms
Pseudomonas aeruginosa Staph aureus including MRSA
Staph epidermidis Brucella
Listeria Mycbacterium tuberculosis
Microbiological features of fluroquinolones
• Rapid bacteriocidal activity
• High potency
• Long post antibiotic effect especially on Pseudomanas, Enterobacteriaceae,
Staphylococcus.
• Low frequency of resistance
• Protects the intestinal streptococci and anerobes which are protective in
function.
• Active against the B lactam aminoglycoside resistant antibiotics.
• Less active under acidic ph.
Indications of fluroquinolones
• Can be used very effectively in the treatment of bone, soft tissue and
wound infections caused by resistant staph and gram negative bacteria.
• For osteomylitis and joint infections prolonged treatment with high
doses is required and high cure rates have been obtained.
• Used along side with metronidazole or clindamycin it is a effective in
surgical infections in diabetic patients.
• Moxifloxacin is primarily used in sinusitis.
• Fluroquinolones are said to cause destruction of weight bearing joins in
pups in lab test conditions . Even so they have been used in children in
India and elsewhere in pressure situations like pseudomonas and multi
resistant typhoid. Though joint pains have occurred there were no
damage to the cartilage. Still manufactures label it as contraindication in
children……
Commercially available fluroquinolones
Ciprofloxacin ciplox 250,500,750mg
tablets.12hrs,200-
500mg/100 mg
i.v
Oral , i.v
Ofloxacin tarivid 100,200,400,m
g
tab,200ml/100
ml i.v 12hrs
Oral , i.v
Sparfloxacin sparta 100, 200mg
tabs 24 hrs
Oral
Moxifloxacin moxif 400mg tabs 24
hrs
Oral
Macrolides
• These antibiotics have a macrocyclic lactone ring with attached rings.
• Isolated from a strain Streptoyces erythreus.
• This species produces a reddish colour and hence the name of the first
antibiotic of this group erythromycin ( erythros “red” )
• Erthromycin is the least toxic antibiotic
Generation of macrolides
• The Older generation :
Erythromycin
Tetracyclin
• The Newer generation :
Roxithromycin
Clarithromycin
Azithromycin
• Miscellaneous Antobiotics :
Clindamycin
Vancomycin
Teicoplanin
The mechanism of action
• The macrolide antibiotics act by inhibiting the protein synthesis.
• They bind to the 50 s subunits of the bacterial ribosome.
• The intracellular concentration of erythromycin that is achieved in gram
positive bacteria is approximately 100 times than that of gram negative
bacteria. So its more effective in the former organism.
• Erythromycin is static in low and cidal at higher concentration.
• The cidal action depends on both the type of the organism and the rate
of multiplication
Spectrum of activity
• Though considered narrow spectrum antibiotic they are active against a
wide range of organisms.
• Str pyogenes
• Str pneumonia
• N gonorrhae
• Closridium
• C diphtheria
• Listeria
Resistance to erythromycin
• All cocci develop resistance to erythromycin.
• The bacteria render them less permeable or acquire the ability to pump
them out.
• Resistant enterobacteriaceae have been found to produce erythromycin
estarase
• Also cross resistance with other macrolides is also seen as their binding
sites are just proximal to each other.
Indications of macrolides
• Erythromycin is well distributed in the soft tissues
• It crosses the blood brain barrier only when there is inflamation
• It penetrates well into abscess.
• It can be used in orodental infections
• Claritromycin and Azitromycin are used in endocarditis prophylaxis.
• They can be used along with erythromycin in orodental infections.
Microbiological features of the newer
macrolides
• These macrolides were produced due to the many adverse effects seen
in the use of erythromycin.
• Roxithromycin is used for skin infections,soft tissue infections.
Has good absorption enterally and good tissue penetration.
• Clarithromycin shows the same resistance pattern as that of
erythromycin.
Can be used in sinusitis,skin structure infections due to strep pyogenes
and some staph aureus.
Commonly available preparations
Erythromycin Erythrocin 250,330,125mg
tab. 125mg/5ml
susp.
Oral
Roxithromycin Roxid 150,300mg tab.
50mg/5ml susp.
Oral
Clarithromycin Clarimac 250,500mg tab Oral
Miscellaneous antibiotics
Clindamycin
• Introduced in 1970.Its a semi synthetic derivative of Lincomycin.
• It is 90% absorbed even when taken with meals.
• It has excellent bone penetrating capability.
• The intraosseous concentration of the drug are nearly equal to those of
the drug in the plasma.
• Though it is effective against gram positive aerobes and gram positive
aerobes and anerobes it is used in specific infections by streptococci,
staphylococci,anerobes like bacteriodes.
• Also used when less toxic antimicrobials are of no use and when
penicillin or a macrolide cannot be used.
• Clindamycin is especially used in cases of refractory bone diseases.
• It is used when there is puruleny ostitis or other bone infections that are
caused by anerobic organisms like Bacteriodes species.
• Important adverse effect of Clindamycin.
• The important adverse effect is on the G.I system.It may cause severe
diarrhea and even fatal pseudomembraneous colitis.
• The colitis occurs mostly with oral consumption but even the par enteral
consumption may cause it because of the enterohepatic circulation of this
drug. The colitis is caused due to the overgrowth of C.difficile.The earliest
sign of colitis is severe diarrhea.
• Disturbances in the host microflora.
• The incidence of the disturbances increases with :
1. The presence of acute pulmonary disease other than tuberculosis.
2. The patients age : less than 3 yrs and greater than 50 yrs.
3. Prolonged duration of antibiotic used.
4. Use of agents with wide range of antibiotic activity.
• The signs and symptoms associated with pseudomembranous colitis are :
1. Pronounced and persistant diarrhea
2. Severe abdominal cramps
3. Fever
4. Appearance of blood and mucous in stools
5. Characteristic appearance of mucosal lesions in the large intestine.
The treatment for pseudomembranous colitis
1. Discontinuation of the offending drug immediately.
2. Correction of water and the electrolyte balance
3. Use of resins like cholestyramine and colestipol which bind to the
toxins.
4. Use of antibiotics to eradicate the offending organisms.
5. Oral metronidazole and vancomycin are used .
6. Anti peristalatic agents should not be used to counteract the
diarrhea because they promote the retention of the clostridial
cytotoxins.
Vancomycin
• This is a glycopeptide antibiotic elaborated from streptomyces orientalis
• Introduced in clinical use in 1956 but the chemical structure was
elucidated only by 1970.
• It is used only in the treatment of infections caused by gram positive
organisms that have become resistant to other antimicrobials.
• However resistance has developed in enterococci.
• It is not absorbed from oral mucosa and G.I tract thus it must be given
paenterally for the treatment for systemic infections.
• It is distributed well in bone and tissues 80% of the drug is excreted
unchanged in the urine.
• The injection of vancomycin i.m causes tissue necrosis and its
administration i.v bolus causes thrombophlebitis so it must be given by slow
infusion.
• The use of this drug in dentistry is restricted to cases of MRSA
• The rapid i.v administration of the drug can lead to hypotension,
tachycardia,and flushing, which gives it the term “Red man syndrome”.
Metronidazole
• It is a synthetic nitromidazole patterned after a naturally occuring
antiparasite substance that was isolated from a streptomyces
species in 1955.
• It is active only against anaerobic bacteria and within this group it is
highly active against :
1. Bacteroides
2. Fusobacterium
3. Campylobacter
4. Clostridium
5. Treponema
• The drug penetrates all the bacteria cells equally well.
• The drug reacts with the bacterial DNA causing inhibition of the DNA
replication and causes fragmentation of the bacterial genome.
• The drug is well absorbed after oral administration and food delays but does
not reduce absorption.
• The drug is disrributed throughout the body and and therapeutic
concentration is achieved in both bone and cerebrospinal fluid.
• In surgery it is used in combination with gentamycin or cephelosporin to
fight anerobic infections.
Anti fungal drugs
• These drugs are use for both superficial and systemic fungal infections.
• From the 1950s there has been a sinister trend of emergence of fungal
infections that are to a large extent iatrogenic.
• These were due to the sudden increase in the use of broad spectrum
antibiotics.
• Also the increased use of indwelling catheters, cytotoxic drugs, use of
implants and most importantly the emergence of AIDS
• Due to this there occurred a breakdown of host defence mechanism and
the fungal infections easily invaded the host living tissue.
Classification of antifungals
• Antibiotics
A. Polyenes : Amphoteracin B, nystatin, hamycin, natamycin
B. Heterocyclic benzoflurans : Griseofulvin
• Antimetabolite : Flucytosine
• Azoles :
A. Imidazole : ( topical ) Cotrimazole, Miconazole, Econazole
( systemic ) Ketoconazole
B. Triazole : ( systemic ) fluconazole, Itraconazole
• Allyamine : Terbinafine
• Others : Benzoic acid, Sodium thiosulphate etc..
In maxillofacial surgery the fungi can be divided into
two broader categories :
• Pathogenic :
• Histoplasmosis
• North American blastomycosis
• South American blastomycosis
• coccydiodomycosis
• Oppurtunistic
•Candidiasis
•Aspergillosis
•Mucormycosis
•Sporotricosis
•Pueumocytosis
• Of these drugs we are going to view in detail the drugs that are
concerned with candidiasis mainly as it is most commonly seen
in our practise.
• The increase in the patients who have AIDS has risen
particularly in the last decade and as the effect of this there
has been also an increase in the prevalence of oppurtunistic
infections as well.
Spectrum of activity of antifungals
• These antifungals are active against a wide range of yeasts and fungi.
• Candida albicans
• Histoplasma capsulatum
• Blastomyces dermatitidis
• Aspergillus
• Sporothix
The antifungal drugs that are active against
Candidiasis.
• These are the first choice of drugs that are active candidiasis :
• They are used for oral/vaginal/cutaneous and disseminated candidiasis.
• The First line of drugs are :
Fluconazole
Nystatin
Clotrimazole
Amphoteracin B
• The second line of drugs :
Itraconazole
Treatment of oral candidiasis
• Candidiasis is the most common type of oro fungal infection.
• Regardless of which drug is used therapy for two weeks is required.
Sometimes even extended treatment may also be required.
• In non – immuno compromised cases :
Cotrimazole oral capsules or Nystatin mouth rinses are preferred.
• In immuno compromised cases :
Oral ketoconazole + Topical nystatin.
( 200 mg ) or
Oral fluconazole + Topical nystatin.
( 100 – 200 mg/day )
• In cases of resistance to these drugs :
Oral Itraconazole ( 200 mg/day).
• In extreme cases :
Amphoteracin B + Flucystosine .
• The occurrence of Lichen planus with candidiasis is common. In such cases :
• Clotrimxazole + topical steroid + Chlorhexidine mouth wash.
Anti viral antimicrobials
Classification
• Anti – herpes virus
Idoxuridine , Acyclovir , Famciclovir , Ganciclovir* , Foscarnet*
• Anti- retrovirus
Zidovudine, Lamivudine, Ritonavir, Indinavir.
• Anti – Influenza virus
Amantadine, Rimantadine
• Non – selective antiviral
• Ribavarine, Lamivudine.
Commonly used drug in Omfs
Acyclovir
This anti viral drug requires a virus specific enzyme for conversion to the
active metabolite that inhibits DNA synthesis and viral replication.
The enzyme that is required for the conversion is Herpes virus specific
thymidine kinase.
The acyclovir tri phosphate then inhibits DNA polymerase competitively
and also stops the lengthening of the DNA strand.
It is active against herpes group of viruses.
Herpes simplex type 1 is the most sensitive followed by type 2.
Treatment of herpes simplex
• The muco cutaneous herpes simplex remains localised to the lips and
gums.
• The treatment includes 10 days of oral acyclovir
• The prophylactic therapy may prevent sun related recurrences.
• In immuno compromised individuals oral or i.v acyclovir ( 15 mg/kg/day )
for 7 days is preferred.
Prophylaxis for HIV infections for health care
professionals.
Types of exposure….
1.Percutaneous – 0.3% probability
eg.. Wide bore needle stick injury, broken glass
vials, scalpel injury, contaminated sharps.
2.Mucous membrane – 0.9%
3.Skin - > 0.9%
Risk of HIV infection after accidental exposure in health care
professionals to bodily fluids not contaminated by visible blood
(urine, saliva, sweat ) is extremely low.
Risk after exposure with large blood volume and severe patients with
advanced disease ishigh
Management
1. Treatment of exposure site
2. Assessment of infection risk
3. Evaluation and testing of source and worker
4. Consulting with infectious disease expert for appropriate
drug selection.
5. Follow up and repeated HIV testing.
The HIV testing is done upto 6 months in at 6 weeks, 12 weeks and 6
months.
Regiment for prophylaxis
• Basic regiment :
It is a two drug regiment :
Combivir - Ziduvurdine + Lamividine
( 300mg ) ( 150mg ) b.d for the duration
Of 4 weeks.
• Extended regiment :
Basic regiment + protease inhibitors
( viracept – 1250 mg ) b.d with food.
If there occurs resistance to the above regiment then consultation to be
done with infectious specialist.
The interval of start of the therapy in animals for the post exposure
treatment is 24 to 36 hours in animal study and no human data
available. Treatment to be started as soon as possible.
Methicillin resistant staph aureus and
vancomycin resistant staph aureus
• Staphylococcus aureus is a gram positive coccus.
• They inhibit the oral cavity in relatively low numbers, there have been
reports of oral infections to be as high as 10 % in deep infections of
odontogenic origin.
• The infections caused by staph aureus are usually localised, with abscess
formation containing purulent exudateand necrotic tissue as in traumatic
skin and post operative wound infections.
• By 1960s : Methicillin, Oxacillin, Cephezolin, penicillin etc became
available.
• By 1970s all the hospitals in the europe and the world had started
reporting about the outbreak of MRSA.
• Nasal carriage as a sourse of MRSA and staph aureus bacteremia was on
the increase by 1990s.
• By 1997 vancomycin was found to be the only drug that was found to be
effective against MRSA but even that started developing resistance when
used over longer periods of time.
• By 1999 resistance to vancomycin started developing in hospitals all over
the world
• A few newer investigational drugs have been developed :
• Oxazolidinone
Linezolid.
• Quinupristine/Dalfopristine
Linezolid
• This is active against MRSA and some VRSA.
• Primarily bacteriostatic but cidal against some streptococci, pneumococci.
• It inhibits bacterial protein synthesis but differntly than the other AMAs
• It binds to the 23s fraction of the 50s ribosome and interfears with the
formation of the tRNA – 70s initiation complex.
• Thus it interfears with the protein synthesis even before it starts.
• It is rapidly and completely absorbed orally
• It can be used for nosocomial drug resistant infections but with prudence as
it is the last line of treatment in such cases.
• 83 – 94% cure rates have been reported.
LIZOLID - 600mg tab b.d
LINOX - 600mg tab b.d
100 ml i.v infusion.
Quinpristine/Dalfopristine
• This is a recently developed combination of two semi synthetic antibiotics
which together exhibit inhibition of bacterial protein synthesis
• It is active against most gram positive cocci including MRSA and some VRSA.
• It is being used in europe for severe nosocomial infections but the drug as
such is not available in India yet.
• Recommendation for preventing the spread of MRSA and VRSA…..
• Standard precaution :
• Wash hands between patients and after removing gloves
• Wear gloves when direct contact with blood, bodily fluid or secretions is
being anticipated.
• Wear mask and goggles/glasses when splashes of bodily fluid anticipated.
• Contact precautions :
• Used when the patient who have been infected or colonised with
epidemologically significant organism through direct contact.
• Place patients ina private room or cohort patients with identical infections
• Wear gloves and gown to enter the room
• Use dedicated thermometers and stethescopes for the patient
• Remove gloves and gown before leaving the room
• Wash hands with microbial soap before leaving the room.
Questions if any

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3.ANTIBIOTICS IN ORAL AND MAXILLOFACIAL SURGERY 1.ppt

  • 1. ANTIBIOTICS IN ORAL AND MAXILLOFACIAL SURGERY. - Dr Sagar Jangam
  • 2. HISTORY OF ANTIBIOTICS. Sir William osler once said *The desire to take medicine is perhaps the greatest feature which distinguishes man from animals * 1550 BC – The writings of ebers papyrus described more than 700 prescriptions. Even in folk medicine drugs like opium (morphine), belladona (atropine), cinchona bark (quinine) etc have been used even in those days. 1877 – Louis pasteur demonstrated coined the word *Antibiosis* 1890-1935 – Ehrlich suggested that dyes may be toxic to pathogenic microorganisms. 1929 – Paul ehilich and Alexander fleming who were doing research in vaccination discovered penicillin accidently. and by 1941 penicillin was available commercially.
  • 3. ANTIMICROBIAL DRUGS. • Drugs in this class are designed to inhibit, kill the infecting organisms and to have no/minimal effect on the recipient. The therapy using these drugs is called chemotherapy meaning *Treatment of systemic infections with specific drugs which selectively suppress infected micro organisms, without significantly affecting the host*
  • 4. CLASSIFICATION Based on type of organism primarily acting against: • Antibacterial : penicillin,aminoglycosides etc • Antifungal : griseofulvin,cotrimazole,amphotericinB • Antiviral : acyclovir,ziduvidine • Antiprotozoal: chloroquine,metronidazole • Antihelmenthic: mebendazole,pyrentel Based on spectrum of activity Narrow spectrum : penecillin g ,streptomycin ,erythromycin Broad spectrum : tetracycline and chloramphenicol Extended spectrum: newer generation narrow spectrum antibiotics like penecillins,cephelosporins and aminoglycosides.
  • 5. Based on the type of action • Bacteriostatic : Sulfonamides Tetracyclines Erythromycin Ethambutol • Some static drugs may become cidal at higher concentrations. •Bactericidal : Penicillin Aminoglycosides Polypeptides Rifampicin Co trimoxozole Cephelosporins Vancomycin Ciprofloxacin • Some cidal drugs may become static.
  • 6. Based on the mechanism of action : A. Inhibit cell wall synthesis : Penicillin, vancomycin, cephelosporins B. Leakage from cell membrane : Polymyxin, bacitracin, amphoteracin B C. Inhibits protein synthesis : Tetracyclines, chloramphenicol,erythromycin D. Misreading of m RNA and affects membrane permeability : Aminogylcosides E. Inhibits DNA gyrase : Flouroquinolones,ciprofloxacin F. Interfers with DNA function : Rifampicin, metronidazole G. Interferes with the DNA synthesis : Acyclovir , zidovudine H. Interferees with the intermediary metabolism : sulfonamides, trimetoprim, ethambutol
  • 7. PENICILLIN • First antibiotic to be used • The molecule consists of fused thiazolide and beta lactam rings with attached side chains. • Highly water soluble and deterioates rapidly under room temperatures. Hence it is dispensed in it’s stable powder form. Can be kept stable in the liquid form at 4 deg c. for 3 days. • The prototype penicillin was penicillin G. • It’s limitations were: Acid instability, Narrow Spectrum, Rapid renal excretion. • Thus penicillin V, extended spectrum and penicillinase resistant were developed.
  • 8. Mechanism of action. • R-C-NH-CH-CH C O=C N COOH O S CH CH 3 3 Region where penicillinase acts. Various derivatives attached here Interfere with synthesis of bacterial cell wall. Inhibition of transpeptidase preventing cross linking of peptidoglycans. Link to penicillin binding proteins found on the cell membrane. Cell wall deficient bacteria multiply. CWD bacteria swell and burst. Gram positive organisms are entirely peptidoglycan linked and are thus susceptible. Rapid cell wall synthesis occurs during multiplication and hence these agents are more active during this phase.
  • 9. Classification of penicillins • Natural penicillins • Penicillin G • Procaine penicillin • Fortified procaine penicillin • Benzathine penicillin • Beta lactam inhibitors: • Clavulanic acid • Sulbactam. Semi synthetic penicilin. 1.Acid resistant : penicillin v. 2.Penicillinase resistant: Methicillin, Cloxacillin. 3.Extended Spectrum : a.Aminopenicillin:ampicillin amoxycillin. b.Carboxypenicillin: Carbencillin, Ticarcilin c.Ureidopenicillin: Piperacillin. d.Mecillinam:
  • 10. Common disease entities for which penicillins are used in OMFS • Abscess. • Gram Positive Bacteraemia. • Endocarditis. • Mastoiditis. • Oro dental infections. • Osteomyelitiis. • Vincent’s infection. • Pharyngitis. • Wound infections. These diseases are caused by a variety of gram positive cocci and bacilli, and a few gram negative organisms. So sensitivity testing is a must.
  • 11. Allergic Reactions. • 1 to 10% of the patients show allergic reactions. • Topical application: most likely to cause sensitization- should not be used. • Life threatening fatalities likely to happen parentrally. • Penicillin g associated with highest drug allergy. • 0.02 % show anaphylaxis of which 5% die of cardiac and respiratory embarrassment. • Foods (milk, beef etc.) exposed to penicilin can sensitise people inadvertently, as this antibiotic is used widely in agriculture. • Thus it is imperative that the patient be tested each time before a regimen.
  • 12. Classification of allergic reactions: • Acute allergic reaction : Anaphylactic shock. • Occur within 30 minutes of administration. • Accelerated allergic reaction : • Occur 30min to 48 hrs after penicillin administration. • Not life threatening, but laryngeal edema may cause respiratory embarrassment. • Delayed allergic reaction : • Takes two or more days to develop. • Most commonly ocuring( 80 to 90% of the cases in which penicillins are used.)
  • 13. Commercialy available penicillin preparations Penicillin G (oral) Pentids 2-8lac units 6- 12 hrs Oral Penicillin G Pfizerpen 10-24 lac units 24 hrs i.v. or i.m. Penicillin G procaine Crystacillin 0-6-4.8 lac units 24 hrs i.m Penicillin G benzathine penidure 0.6-2.4 lac units 24 hrs i.M or i.v Fortified penicillin Fortified pp 3 lac procaine+ 1 lac pen G i.M or i.v
  • 14. Semi synthetic penicillins Penicillin v Crystapen v 250-500 mgs 6hrs oral Cloxicillin klox 250-500mgs 6 hrs Oral, i.m, i.v Ampicillin Ampilin ,roscillin 500mgs-2 gms 6hrs Oral, i.m, i.v Amoxicillin novamox 250mg-1gm 6 hrs oral Carbenecilin carbellin 1-5 gms 6 hrs i.M , i.v Pipericillin piperapen 1-2.5gms 6 hrs i.m, above 2 gm i.v
  • 15. Beta lactamase inhibitors • These drugs bind to the penicillanase enzyme rendering them inactive against the beta lactam ring. • The bond is irreversible and hence are called as suicide inhibitors • Commercially available preparations are combines with penicillins
  • 16. Commercially available preparations Clavulanic acid Augmentin Amoxycillin- 250mgs +clavulanic acid -125 mgs 6 hrs Oral, Sulbactum sulbasam Ampicillin 1 gm+ sulbactum 500mgs 6 hrs Deep i.m, i.v
  • 17. Spectrum of activity of penicillins • Naturally occurring penicillins and penicillin v • Gram positive cocci and bacilli • Also gram negative neisseira • Sensitive to spirochetes • Resistance to penicillanase producing organisms • Extended spectrum penicillins • All above mentioned organisms and gram negative organisms like H influenzae, E coli, Salmonella, shigella, Proteus • Amoxycillin is better tolerated orally but not as potent as ampicilin
  • 18. Penicillinase resistant penicillin These drugs have side chains that protect them from attack of penicillinases Penicillin resistant staphylococcal infections. It is not active against MRSA and VRSA. Carboxy penicillin and urido penicillin(pipericillin) They are active against pseudomonas and klebsiella.
  • 19. CEPHELOSPORINS • It is also a beta lactam antibiotic • These drugs bind to different protein in the cell membrane than that of penicillins • Another reason for limited cross sensitivity and a variation in the spectrum amongst this family of drugs is that different molecules of cephelosporins bind to different protein sites. • There is 10% chance of cross resistance to penicillin. • They are subdivided into four generations and the first are more active against gram positive and the later are more active against gram negative organisms.
  • 20. Generations of cephelosporins • First generation cephelosporins Cefadroxil Cephelexin • Second generation cephelosporins Cefuroxime Cefaclor • Third generation cephelosporin Cefetaxime Ceftriaxone Ceftazidine Cefoperazone Cefixime • Fourth generation cephelosporins Cefepime Cefpirome
  • 21. Spectrum of activity of first generation • Generally have the same spectrum as that of penicillins • Some activity against klibsiella and e.coli • Cefedroxil is a specific second line of drug used in bacterial endocarditis
  • 22. Spectrum of activity of second generation •Highly resistant to penicillinase producing organisms •Has better gram negative activity as compared to the first generation •It is also active against some anerobes •It is thus used extensively in surgical infections of mixed nature.
  • 23. Spectrum of activity of third generation •Excellent activity against gram negative organism •Not so efficient against gram positive organisms •Highly resistant against beta lactamases •The newer drugs have a high activity against pseudomonas (ceftazidime, cefoperazone)
  • 24. Spectrum of activity of fourth generation • They have better activity against some organisms resistant to older generation cefelosporins • They have superior action on pseudomonas and staphylococcus
  • 25. Commercially available cephalosporins Cephalexin spoidex 250-1gm 6hrs oral Cefedroxil droxil 500mg-1gm 8hrs oral Cefuroxime cefogin 750mgs-1.5 8hrs i.m, i.v Cefeclor keflor 250mgs 8hrs oral Cefotaxime Omnatax 1-2gms 8hrs i.m, i.v Ceftriaxone monotax 1-2gms 24hrs i.m, i.v Ceftadizime cefazid 500mgs-2gms 8hrs i.m, i.v Cefopirazone magnamicin 250mgs-2gms 8hrs i.m, i.v Cefexime orfix 250-400mgs 8hrs oral Cefipime kefage 1-2gms 8hrs i.v,i.m
  • 26. Indications of cephalosporins • Patients who show minor allergic reaction to penicillin,it can be used with caution. • Gram negative soft tissue infections and urinary tract infections • Iatrogenic infections • Penicillanase producing staphylococcal infections • Surgical prophylaxis • Other mixed infections
  • 27. Aminoglycoside Antibiotics •Aminoglycosides were drugs produced not by chance like penicillin but were produced in a deliberate search for products effective against gram negative bacteria. •Streptomycin was the first drug to be produced by Waksman in 1944. •All aminoglycosides are produced by soil actinomycetes.
  • 28. Important properties of aminoglycosides • They are highly water soluble and are stable for months • They are not absorbed orally and do not penetrate brain or csf. • They are excreted in the urine in the unchanged form • All are bacteriocidal and are more active in alkaline ph. • They are active against gram negative bacilli. • They have only partial cross resistance so an organism resistant to one aminoglycosides may still respond to another. • They have a very narrow margin of safety between therapeutic and toxic concentrations. • They all exhibit ototoicity and nephro toxicity.
  • 29. Mechanism of action • They are transported in two main steps : A. Transport of the drug through the bacterial cell wall. B. Binding to the ribosomes resulting in inhibition of protein synthesis. 1.They diffuse through the outer coat of gram negative bacteria through their porin channel 2.Entry to the cytoplasm is carrier mediated. 3.Entry is mediated by maintenance of polarized membrane and is also oxygen dependent. Thus penetration is dependent on the presence of oxygen and so they are not active in big abscess. Also the penetration is also favored by high ph(20 times more active in alkaline medium than acid medium.)
  • 30. 4.Once inside streptomycin binds to the 30s ribosomes whereas the others bind to 50s ribosomes and 30s-50s interface. 5.This causes the misreading of the mRNA codon. But the cidal action of these antibiotics is mainly caused by the changes caused in the bacterial cell membrane. They incorporate defective proteins in the cell membrane which causes the leak out of ions, aminoacids and even protein t cause cell death. The cidal action is concentration dependent and is related to the peak concentration of the drug to the minimum inhibitory concentration values.
  • 31. Post antibiotic effect This is after a brief exposure to the antibiotic if the organism is placed in a antibiotic free medium it starts multiplying again but after a lag phase. The length of this lag phase depends both on the antibiotic as well as the bacteria itself. So it is argued that though the half life of aminoglycosides is (2 – 4 hrs) a single injection of the antibiotic is more effective and also less toxic than 3 divided doses which are used conventionally.
  • 32. Spectrum of activity of aminoglycosides • Active against P aeruginosa, klebsiella, proteus • Gentamycin is added to penicillin or a third generation cephelosporin in treating serious infections. • Tobramycins only use is in the treatment of serious proteus and pseudomonas infections. • Amikacin is used as a reserve drug for hospital acquired gram negative bacilli infections and when resistance has developed to both gentamycin and tobramycin.
  • 33. Commercially available aminoglycosides Sreptomycin Ambysterin-s 1gm 8 hrs Above 50yrs( 0.75gms) i.m Gentamycin Garamycin 20- 240 mg /vial calculated for pt. i.m, i.v Tobramycin tobacin 3-5mg/kg in 1-3 divided doses/day i.v Netilmicin netromycin 4-6mg/kg/day in 3 divided doses i.v Neomycin nebasulf Neomycin-5mg Bacitracin-250u Sulfacitamide- 60mg/gm Surface application
  • 34. Newer drugs in aminoglycosides •Gentamycin PMMA ( poly methylmethacrylate) This is a new drug delivery system uded in osteomylitis. This consists of a small acrylic beads each impregnated with 7.5mg gentamycin sulphate and threaded over a surgical grade wire. when this is placed after the removal of the sequestrum for 10 days high cure rates have been achieved.
  • 35. Dose regulation • The dose must be presicely calculated as it has a narrow margin of safety. • Average adult dosage : 3 – 5mg/kg/day i.m in a single dose • The creatine clearance is also taken into account. • Normal adult creatine clearance : about 100ml/min • Loading dose need not be reduced ( unless edema is present) but the maintanence dose has to be reduced. • Cl clr(ml/min) Reduce dose by 50-70 1.5times 30-50 2 times 10-30 3 times 05-10 6 times
  • 36. Indications and interactions • To be avoided during pregnancy as there is risk of fetal ototoxicity • Avoided with other ototoxic drugs like minocycline and high ceiling diuretics. • To be avoided with other nephrotoxic drugs like vancomycin, amphoteracin B. • Should be used cautiously in patients past middle age and those who have kidney damage • Aminoglycosides should not be mixed with any other drug in the same syringe/infusion bottle.
  • 37. Quinolones • Entirely synthetic antimicrobials. • Nalidixic acid was the first to be introduced in early 1960. • In 1980s fluroquinolones were formulated . • They had high potency, expanded spectrum ,slow resistance development, better tissue penetration and good tolerability.
  • 38. Generations of flouroquinolones •First generation : • Norfloxacin • Ofloxacin • Ciprofloxacin • Perfloxacin •Second generation : • Lomefloxacin • Sparfloxacin • Levofloxacin • Gatifloxacin • Moxifloxacin
  • 39. Mechanism of action • Inhibits enzyme DNA gyrase which nicks the double stranded DNA introduces negative supercoils and then reseals the nicked ends. • The DNA gyrase consists of two A and two B subunits. • Under normal circumstances Subunit A nicks the DNA.., Subunit B introduces the negative supercoil..,Subunit A again reseals the DNA. • This drug has a very high affinity to the Subunit A so it interferes with the cutting and the resealing action thus faulting the bacterial replication. Its bacteriocidal action is due to the digestion of the DNA by the exonucleases whose production is signalled by the damaged DNA.
  • 40. Spectrum of activity of fluroquinolones • Highly susceptible organisms E.coli Shigella K.pneumonia H.influenzae Enterobacter Proteus Salmonella Yersinia enterocolitica • Moderately susceptible organisms Pseudomonas aeruginosa Staph aureus including MRSA Staph epidermidis Brucella Listeria Mycbacterium tuberculosis
  • 41. Microbiological features of fluroquinolones • Rapid bacteriocidal activity • High potency • Long post antibiotic effect especially on Pseudomanas, Enterobacteriaceae, Staphylococcus. • Low frequency of resistance • Protects the intestinal streptococci and anerobes which are protective in function. • Active against the B lactam aminoglycoside resistant antibiotics. • Less active under acidic ph.
  • 42. Indications of fluroquinolones • Can be used very effectively in the treatment of bone, soft tissue and wound infections caused by resistant staph and gram negative bacteria. • For osteomylitis and joint infections prolonged treatment with high doses is required and high cure rates have been obtained. • Used along side with metronidazole or clindamycin it is a effective in surgical infections in diabetic patients. • Moxifloxacin is primarily used in sinusitis. • Fluroquinolones are said to cause destruction of weight bearing joins in pups in lab test conditions . Even so they have been used in children in India and elsewhere in pressure situations like pseudomonas and multi resistant typhoid. Though joint pains have occurred there were no damage to the cartilage. Still manufactures label it as contraindication in children……
  • 43. Commercially available fluroquinolones Ciprofloxacin ciplox 250,500,750mg tablets.12hrs,200- 500mg/100 mg i.v Oral , i.v Ofloxacin tarivid 100,200,400,m g tab,200ml/100 ml i.v 12hrs Oral , i.v Sparfloxacin sparta 100, 200mg tabs 24 hrs Oral Moxifloxacin moxif 400mg tabs 24 hrs Oral
  • 44. Macrolides • These antibiotics have a macrocyclic lactone ring with attached rings. • Isolated from a strain Streptoyces erythreus. • This species produces a reddish colour and hence the name of the first antibiotic of this group erythromycin ( erythros “red” ) • Erthromycin is the least toxic antibiotic
  • 45. Generation of macrolides • The Older generation : Erythromycin Tetracyclin • The Newer generation : Roxithromycin Clarithromycin Azithromycin • Miscellaneous Antobiotics : Clindamycin Vancomycin Teicoplanin
  • 46. The mechanism of action • The macrolide antibiotics act by inhibiting the protein synthesis. • They bind to the 50 s subunits of the bacterial ribosome. • The intracellular concentration of erythromycin that is achieved in gram positive bacteria is approximately 100 times than that of gram negative bacteria. So its more effective in the former organism. • Erythromycin is static in low and cidal at higher concentration. • The cidal action depends on both the type of the organism and the rate of multiplication
  • 47. Spectrum of activity • Though considered narrow spectrum antibiotic they are active against a wide range of organisms. • Str pyogenes • Str pneumonia • N gonorrhae • Closridium • C diphtheria • Listeria
  • 48. Resistance to erythromycin • All cocci develop resistance to erythromycin. • The bacteria render them less permeable or acquire the ability to pump them out. • Resistant enterobacteriaceae have been found to produce erythromycin estarase • Also cross resistance with other macrolides is also seen as their binding sites are just proximal to each other.
  • 49. Indications of macrolides • Erythromycin is well distributed in the soft tissues • It crosses the blood brain barrier only when there is inflamation • It penetrates well into abscess. • It can be used in orodental infections • Claritromycin and Azitromycin are used in endocarditis prophylaxis. • They can be used along with erythromycin in orodental infections.
  • 50. Microbiological features of the newer macrolides • These macrolides were produced due to the many adverse effects seen in the use of erythromycin. • Roxithromycin is used for skin infections,soft tissue infections. Has good absorption enterally and good tissue penetration. • Clarithromycin shows the same resistance pattern as that of erythromycin. Can be used in sinusitis,skin structure infections due to strep pyogenes and some staph aureus.
  • 51. Commonly available preparations Erythromycin Erythrocin 250,330,125mg tab. 125mg/5ml susp. Oral Roxithromycin Roxid 150,300mg tab. 50mg/5ml susp. Oral Clarithromycin Clarimac 250,500mg tab Oral
  • 52. Miscellaneous antibiotics Clindamycin • Introduced in 1970.Its a semi synthetic derivative of Lincomycin. • It is 90% absorbed even when taken with meals. • It has excellent bone penetrating capability. • The intraosseous concentration of the drug are nearly equal to those of the drug in the plasma. • Though it is effective against gram positive aerobes and gram positive aerobes and anerobes it is used in specific infections by streptococci, staphylococci,anerobes like bacteriodes. • Also used when less toxic antimicrobials are of no use and when penicillin or a macrolide cannot be used.
  • 53. • Clindamycin is especially used in cases of refractory bone diseases. • It is used when there is puruleny ostitis or other bone infections that are caused by anerobic organisms like Bacteriodes species. • Important adverse effect of Clindamycin. • The important adverse effect is on the G.I system.It may cause severe diarrhea and even fatal pseudomembraneous colitis. • The colitis occurs mostly with oral consumption but even the par enteral consumption may cause it because of the enterohepatic circulation of this drug. The colitis is caused due to the overgrowth of C.difficile.The earliest sign of colitis is severe diarrhea.
  • 54. • Disturbances in the host microflora. • The incidence of the disturbances increases with : 1. The presence of acute pulmonary disease other than tuberculosis. 2. The patients age : less than 3 yrs and greater than 50 yrs. 3. Prolonged duration of antibiotic used. 4. Use of agents with wide range of antibiotic activity. • The signs and symptoms associated with pseudomembranous colitis are : 1. Pronounced and persistant diarrhea 2. Severe abdominal cramps 3. Fever 4. Appearance of blood and mucous in stools 5. Characteristic appearance of mucosal lesions in the large intestine.
  • 55. The treatment for pseudomembranous colitis 1. Discontinuation of the offending drug immediately. 2. Correction of water and the electrolyte balance 3. Use of resins like cholestyramine and colestipol which bind to the toxins. 4. Use of antibiotics to eradicate the offending organisms. 5. Oral metronidazole and vancomycin are used . 6. Anti peristalatic agents should not be used to counteract the diarrhea because they promote the retention of the clostridial cytotoxins.
  • 56. Vancomycin • This is a glycopeptide antibiotic elaborated from streptomyces orientalis • Introduced in clinical use in 1956 but the chemical structure was elucidated only by 1970. • It is used only in the treatment of infections caused by gram positive organisms that have become resistant to other antimicrobials. • However resistance has developed in enterococci. • It is not absorbed from oral mucosa and G.I tract thus it must be given paenterally for the treatment for systemic infections. • It is distributed well in bone and tissues 80% of the drug is excreted unchanged in the urine.
  • 57. • The injection of vancomycin i.m causes tissue necrosis and its administration i.v bolus causes thrombophlebitis so it must be given by slow infusion. • The use of this drug in dentistry is restricted to cases of MRSA • The rapid i.v administration of the drug can lead to hypotension, tachycardia,and flushing, which gives it the term “Red man syndrome”.
  • 58. Metronidazole • It is a synthetic nitromidazole patterned after a naturally occuring antiparasite substance that was isolated from a streptomyces species in 1955. • It is active only against anaerobic bacteria and within this group it is highly active against : 1. Bacteroides 2. Fusobacterium 3. Campylobacter 4. Clostridium 5. Treponema
  • 59. • The drug penetrates all the bacteria cells equally well. • The drug reacts with the bacterial DNA causing inhibition of the DNA replication and causes fragmentation of the bacterial genome. • The drug is well absorbed after oral administration and food delays but does not reduce absorption. • The drug is disrributed throughout the body and and therapeutic concentration is achieved in both bone and cerebrospinal fluid. • In surgery it is used in combination with gentamycin or cephelosporin to fight anerobic infections.
  • 60. Anti fungal drugs • These drugs are use for both superficial and systemic fungal infections. • From the 1950s there has been a sinister trend of emergence of fungal infections that are to a large extent iatrogenic. • These were due to the sudden increase in the use of broad spectrum antibiotics. • Also the increased use of indwelling catheters, cytotoxic drugs, use of implants and most importantly the emergence of AIDS • Due to this there occurred a breakdown of host defence mechanism and the fungal infections easily invaded the host living tissue.
  • 61. Classification of antifungals • Antibiotics A. Polyenes : Amphoteracin B, nystatin, hamycin, natamycin B. Heterocyclic benzoflurans : Griseofulvin • Antimetabolite : Flucytosine • Azoles : A. Imidazole : ( topical ) Cotrimazole, Miconazole, Econazole ( systemic ) Ketoconazole B. Triazole : ( systemic ) fluconazole, Itraconazole • Allyamine : Terbinafine • Others : Benzoic acid, Sodium thiosulphate etc..
  • 62. In maxillofacial surgery the fungi can be divided into two broader categories : • Pathogenic : • Histoplasmosis • North American blastomycosis • South American blastomycosis • coccydiodomycosis • Oppurtunistic •Candidiasis •Aspergillosis •Mucormycosis •Sporotricosis •Pueumocytosis
  • 63. • Of these drugs we are going to view in detail the drugs that are concerned with candidiasis mainly as it is most commonly seen in our practise. • The increase in the patients who have AIDS has risen particularly in the last decade and as the effect of this there has been also an increase in the prevalence of oppurtunistic infections as well.
  • 64. Spectrum of activity of antifungals • These antifungals are active against a wide range of yeasts and fungi. • Candida albicans • Histoplasma capsulatum • Blastomyces dermatitidis • Aspergillus • Sporothix
  • 65. The antifungal drugs that are active against Candidiasis. • These are the first choice of drugs that are active candidiasis : • They are used for oral/vaginal/cutaneous and disseminated candidiasis. • The First line of drugs are : Fluconazole Nystatin Clotrimazole Amphoteracin B • The second line of drugs : Itraconazole
  • 66. Treatment of oral candidiasis • Candidiasis is the most common type of oro fungal infection. • Regardless of which drug is used therapy for two weeks is required. Sometimes even extended treatment may also be required. • In non – immuno compromised cases : Cotrimazole oral capsules or Nystatin mouth rinses are preferred. • In immuno compromised cases : Oral ketoconazole + Topical nystatin. ( 200 mg ) or Oral fluconazole + Topical nystatin. ( 100 – 200 mg/day ) • In cases of resistance to these drugs : Oral Itraconazole ( 200 mg/day).
  • 67. • In extreme cases : Amphoteracin B + Flucystosine . • The occurrence of Lichen planus with candidiasis is common. In such cases : • Clotrimxazole + topical steroid + Chlorhexidine mouth wash.
  • 68. Anti viral antimicrobials Classification • Anti – herpes virus Idoxuridine , Acyclovir , Famciclovir , Ganciclovir* , Foscarnet* • Anti- retrovirus Zidovudine, Lamivudine, Ritonavir, Indinavir. • Anti – Influenza virus Amantadine, Rimantadine • Non – selective antiviral • Ribavarine, Lamivudine.
  • 69. Commonly used drug in Omfs Acyclovir This anti viral drug requires a virus specific enzyme for conversion to the active metabolite that inhibits DNA synthesis and viral replication. The enzyme that is required for the conversion is Herpes virus specific thymidine kinase. The acyclovir tri phosphate then inhibits DNA polymerase competitively and also stops the lengthening of the DNA strand. It is active against herpes group of viruses. Herpes simplex type 1 is the most sensitive followed by type 2.
  • 70. Treatment of herpes simplex • The muco cutaneous herpes simplex remains localised to the lips and gums. • The treatment includes 10 days of oral acyclovir • The prophylactic therapy may prevent sun related recurrences. • In immuno compromised individuals oral or i.v acyclovir ( 15 mg/kg/day ) for 7 days is preferred.
  • 71. Prophylaxis for HIV infections for health care professionals. Types of exposure…. 1.Percutaneous – 0.3% probability eg.. Wide bore needle stick injury, broken glass vials, scalpel injury, contaminated sharps. 2.Mucous membrane – 0.9% 3.Skin - > 0.9% Risk of HIV infection after accidental exposure in health care professionals to bodily fluids not contaminated by visible blood (urine, saliva, sweat ) is extremely low. Risk after exposure with large blood volume and severe patients with advanced disease ishigh
  • 72. Management 1. Treatment of exposure site 2. Assessment of infection risk 3. Evaluation and testing of source and worker 4. Consulting with infectious disease expert for appropriate drug selection. 5. Follow up and repeated HIV testing. The HIV testing is done upto 6 months in at 6 weeks, 12 weeks and 6 months.
  • 73. Regiment for prophylaxis • Basic regiment : It is a two drug regiment : Combivir - Ziduvurdine + Lamividine ( 300mg ) ( 150mg ) b.d for the duration Of 4 weeks. • Extended regiment : Basic regiment + protease inhibitors ( viracept – 1250 mg ) b.d with food. If there occurs resistance to the above regiment then consultation to be done with infectious specialist. The interval of start of the therapy in animals for the post exposure treatment is 24 to 36 hours in animal study and no human data available. Treatment to be started as soon as possible.
  • 74. Methicillin resistant staph aureus and vancomycin resistant staph aureus • Staphylococcus aureus is a gram positive coccus. • They inhibit the oral cavity in relatively low numbers, there have been reports of oral infections to be as high as 10 % in deep infections of odontogenic origin. • The infections caused by staph aureus are usually localised, with abscess formation containing purulent exudateand necrotic tissue as in traumatic skin and post operative wound infections. • By 1960s : Methicillin, Oxacillin, Cephezolin, penicillin etc became available. • By 1970s all the hospitals in the europe and the world had started reporting about the outbreak of MRSA. • Nasal carriage as a sourse of MRSA and staph aureus bacteremia was on the increase by 1990s.
  • 75. • By 1997 vancomycin was found to be the only drug that was found to be effective against MRSA but even that started developing resistance when used over longer periods of time. • By 1999 resistance to vancomycin started developing in hospitals all over the world • A few newer investigational drugs have been developed : • Oxazolidinone Linezolid. • Quinupristine/Dalfopristine Linezolid • This is active against MRSA and some VRSA. • Primarily bacteriostatic but cidal against some streptococci, pneumococci. • It inhibits bacterial protein synthesis but differntly than the other AMAs
  • 76. • It binds to the 23s fraction of the 50s ribosome and interfears with the formation of the tRNA – 70s initiation complex. • Thus it interfears with the protein synthesis even before it starts. • It is rapidly and completely absorbed orally • It can be used for nosocomial drug resistant infections but with prudence as it is the last line of treatment in such cases. • 83 – 94% cure rates have been reported. LIZOLID - 600mg tab b.d LINOX - 600mg tab b.d 100 ml i.v infusion. Quinpristine/Dalfopristine • This is a recently developed combination of two semi synthetic antibiotics which together exhibit inhibition of bacterial protein synthesis
  • 77. • It is active against most gram positive cocci including MRSA and some VRSA. • It is being used in europe for severe nosocomial infections but the drug as such is not available in India yet. • Recommendation for preventing the spread of MRSA and VRSA….. • Standard precaution : • Wash hands between patients and after removing gloves • Wear gloves when direct contact with blood, bodily fluid or secretions is being anticipated. • Wear mask and goggles/glasses when splashes of bodily fluid anticipated. • Contact precautions : • Used when the patient who have been infected or colonised with epidemologically significant organism through direct contact.
  • 78. • Place patients ina private room or cohort patients with identical infections • Wear gloves and gown to enter the room • Use dedicated thermometers and stethescopes for the patient • Remove gloves and gown before leaving the room • Wash hands with microbial soap before leaving the room.