antibiotics and antibacterial drugs
TRANSCRIPT
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ANTIBIOTICSANTIBIOTICSDr. V.RAMKUMAR
CONSULTANT DENTAL &FACIOMAXILOFACIAL SURGEON
REG. NO.4118. TAMILNADU- INDIA( ASIA)
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Principles of rational antibiotic therapy
• Presence of substantiated indications for prescription of an antibiotic
• Choosing of the most effective and the least toxic drug, in time administration
• Introduction of optimal doses with optimal frequency, taking into consideration complexity of the disease
• Choosing of the optimal way of introduction• Estimation of duration of treatment• Control after treatment• Monitoring and prophylaxis of negative side effects• Decision on expediency of combined antibiotic therapy
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Mechanism of the antibioticsMechanism of the antibiotics
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ANTIBIOTICS• Beta-lactam antibiotics:• А. Penicillins• Б. Inhibitors of beta-lactamases and combined drugs, • В. Cephalosporins• Г. Monobactams• Д. Tienamycin (carbapenems).• Macrolides, azalides, streptogramins, prystinamycines.• Linkozamides.• Tetracyclines.• Aminoglycosides.• Chloramphenicols.• Glycopeptides.• Cyclic polipeptides (polimixins).• Other antibiotics
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ANTIBIOTICS
Dose-dependent Time-dependent
Antibacterial effect directly depends on their concentrations in the locus of inflammation
(high doses 1-2 times/24h)
Aminoglycosides
Fluoroqinolones
Metronidazol
Amphotericin B
Effectiveness depends on a period of time, during which concentration in blood overwhelms MIC for a particular causative agent
(constant i.v. infusion or 3-6 times/24h)
Beta-lactames
Glycopeptides
Macrolides
Linkozamides
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PENICILLINS Natural (biosynthetic) penicillins:
• benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), novocain salt of benzylpenicillin (benzylpenicillin procain), bicillin-1 (benzatyn benzylpenicillin), bicillin-3, bicillin-5.
Semisynthetic penicillins:• 1 antistaphylococci penicillinase resistant penicillins –
izoxazolil-penicillins (oxacillin, dicloxacillin, methicillin);• 2 of a spread spectrum – aminopenicillins (ampicillin,
amoxicillin); • 3 antipseudomonade – carboxypenicillins (carbenicillin,
ticarcillin); ureidopenicillins (azlocillin, piperacillin, sulbenicillin);• 4 combined with inhibitors of beta-lactamases -
“protected” penicillins (amoxicillin/clavulanate, ampicillin/sulbactam, ticarcillin/clavulanate, piperacillin/tazobactam).
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Nucleus of penicillin moleculeL – beta-lactame ring, T – thiazoline ring
N
TL
S
CO
OH
CH3
CH3
O
H2N
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Mechanism of penicillins actionMechanism of penicillins action
They form complexes with enzymes - trans- and carboxypeptidases (PCP), which control synthesis of peptidoglycan – component of cell-wall of microorganisms
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Spectrum of action of biosynthetic penicllins
Gram-positive microorganisms
Gram-negative microorganisms
Streptococci
Bacillus anthracis
Causative agents of tetanus, gas gangrene
Actinomycets
Listeria
Gonococci
Meningococci
Moraxella
Causative agent of syphilis
Leptospiras
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Complications of biosynthetic penicillins
• Allergic reactions (10 %)• Endotoxic shock• Disorders of electrolyte balance• Neurotoxic reactions (in using of big doses)
– encephalopathy (hyperreflexia, seizures, hallucinations, coma)
• Daily dose of BP during intratecal introduction should not overcome 10 000 U
(5 000 U – for children)• Interstitial nephritis
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OxacillinOxacillin
Antistaphylococci penicillinase-resistant semisynthetic penicillin, acid stable
Administration: intramuscular, intravenously, oraly 3-6-8 g/24 hours (4-6 times of injections)
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.
Spectrum of action of aminopecillins (ampicillin, amoxicillin)
wide spectrum, destroyed by beta-lactamases
Influence on: streptococci, Haemophilus influenzae, causative agent of wooping cough, gonococci, meningococci, proteus,
Escherichia coli, salmonella, shigella
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Ampicillin
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Amoxicillin
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Differences between ampicillin and amoxicillin Differences between ampicillin and amoxicillin
Parameters
Ampicillin Amoxycillin
Activity towdards
- pneumococci
- H. pylori
- salmonella
- shigella
Bioavailability after oral administration
Influence of food on bioavailability
Level in sputum
Level in urine
Appearance of diarrhea
++
+
++/+++
+++
40 %
dicreases in 2 times
low
high
frequently
+++
+++
+++
+
90 %
no influence
high
very high
rarely
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Indications for administration of amoxicillin Localisation of ifection Drug of choice Alternative drug
Respiratory tracts Acute midlle otitis
Bacterial sinusitit
Acute bronchitits
Extrahospital pneumonia of light or medium-severe complexity
Acute pharingitis
Chronical bronchitis
Kidneys and urinary tracts
Acute pielonephritis
Acute cystitis
Bacteriouria in children and pregnant women
Chronical pielonephritis
Acute prostatitis
Gonorrhea
Digestive tract Cholangitis, cholecystitis
Typhoid fever
Other pathology Borreliosis Leptospirosis
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Side effects of semisynthetic penicillins
• Irritation of mucous membrane of digestive tract (diarrhea)
• Disbacteriosis• Superinfection (colonizing of gut with Candida fungi,
enterococci, Pseudomonas aeruginosa, clostridia)• Pain in injection area, aseptical inflammation,
phlebitis• Allergic reactions• Granulocytopenia (oxacillin)• Reduction of platelets agregation (ampicillin)• Disorders of liver function• Encephalopathy (in introduction of high doses)
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Inhibitors of beta-lactamases
Clavulanic acid Sulbactam
Tazobactam
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Unasyn (ampicillin/sulbactam)
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Inhibitor-protected (“screened”, “protected”) Inhibitor-protected (“screened”, “protected”) penicillinspenicillins
Amoxicillin/clavulanateAmoxicillin/clavulanate (amoxyclav, augmentin)(amoxyclav, augmentin)
AmpicillinAmpicillin/sulbactam/sulbactam (sultamycillin, unasin)(sultamycillin, unasin) TicarcillinTicarcillin/clavulanate/clavulanate
(timentin)(timentin) PiperacillinPiperacillin/tazobactam/tazobactam
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Structure of cephalosporinsL – beta-lactame ring, D – dihydrothiazine ring
CH2 O CO CH3
C
O
H2N
O
OH
S
L D
N
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Classification of cephalosporinsClassification of cephalosporins
Way of introduction
Generation of cephalosporin antibiotics
first I second II third III fourth IV
Injection Cefaloridin
Cefadroxil*
Cefazolin*
Cefalexin*
Cephradin*
Cefamandole* Cefoxytyn*
Cefuroxime*
Cefotaxime*
Ceftriaxone*
Cefoperazone*
Ceftazidime*
Cefpirome*
Cefepime*
Oral Cephalexin *
Cefadroxil*
Cefuroxime axetyl*
Cefaclor *
Cefixime *
Ceftibuten * -
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Cefazolin-sodium (C I)
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Cezolin (Cefazolin, C I)
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Cefalexin ( C I)
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Zinnat (Cefuroxime, C II)
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Cefotaxime (C III)
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Claphoran (cefotaxime, C III)
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Cefobid (Cefoperazone, C III)
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Antimicrobial spectrum of cephalosporins
Generation of cephalosporins
Active towards Stability towards beta-lactamase
Gram-positive bacteria
Gram-negative bacteria
Staphylo cocci
Gram-negative bacteria
І +++ +/- ++ - ІІ ++ + ++ +/-
ІІІ + +++ + +
ІV ++ +++ ++ ++
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Complications, caused by cephalosporins
• Irritation of mucous membrane of digestive tract, infiltrates after intromuscular introduction , phlebitis after inrtavenous introduction
• Disbacteriosis, superinfection• Allergic reactions, including cross allergy with
penicillins• Granulocytopenia (in case of treatment during more
than 2 weeks)• Hemorrhages (inhibition of synthesis of factors of
blood coagulation in liver) – cephalosporins ІІІ• Nephrotoxicity (accumulation in epithilial cells of
kidney canalicules)• Encephalopathy (hyperreflexia, seizures, coma)
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Cephalosporines Cephalosporines
NNot recommendedot recommended to combine with other nephrotoxic drugs
(aminoglycosides)
ContraindicatedContraindicated to combine with loop diuretics (furosemid,
etacrinic acid)
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MonobactamsMonobactamsAztreonam
Action spectrum - Gram (-) bacteria, including Escherichia coli, Clebsiellas, Proteus, Haemophilus influenzae (activity is equal to the activity of cephaloporins of third generation)
Ways of introduction: oral (20% are being absorbed), intramuscular, intravenous
Clinical uses: sepsis, infection of urinary tract, soft tissues, meningitis and others (often combined with aminoglycosides , clindamycin, metronidazole, vankomycin).
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Carbapenems (tienamytsin)Carbapenems (tienamytsin)
Tienam (imipenem + cylastatin) Tienam (imipenem + cylastatin)
MeropenemMeropenem
The widest spectrum of antibacterial action most of aerobe and anaerobe Gram (+) and Gram (-) bacteria, including those which produce beta-lactamase
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І. Natural substances: erythromycin, oleandomycin, spiramycin, jozamycin, midecamycin.
ІІ. Semi-synthetic substances: roxythromycin, clarithromycin, flurythromycin, dyrythromycin, miokamycin, rokitamycin.
III. Azalides (neutrogen atom is introduced in lacton ring): azithromycin.
CLASSIFICATION OF MACROLIDES
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Erythromycin
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Macropen (midecamycin)
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Sumamed (azithromycin)
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spectrum of action of maclrolides and azalides
• staphylo-, strepto-, hono-, anaerobe cocci, enterobacteria
• H.influenzae (clarythromycin, azithromycin)
• intracellular situated microorganisms (strains of Helicobacter, Chlamydia, Legionellа, M. pneumoniae, U. urealyticum etc.)
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Pharmacokinetics of macrolides
Quiclkly and fully distributed through the tissues (do not pass through HEB OR
BBB)Correlation concentration tissues/blood:• Erythromycin – (5-10) : 1• Azithromycin – (100-500) : 1• Their concentration in phagocyting
cells prevails concentration in blood pasma in 12-20 times, they get accumulated in source of inflammation - macrolides paradoxis
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Indications for usage of macrolides and azalides
LOR- infections, infections of upper respiratory tracts, gynecological infections, skin and soft tissues infections; ulcer disease; dyphteria; whooping-cough; honorrhea; syphilis; typhoid fever (azithromycin).
Drugs of choice for: mycoplasma, chlamidia, legionella pneumonia
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Side affects of macrolides
• Dispeptic disorders, disbacteriosis, superinfection• Cholestasis, cholestatic jaundice (erythromycin)• Depression of liver microsome enzyme activity
(erythromycin, oleandomycin can not be combined with theophylline, ergot alkaloids, carbamazepine)
• Development of resistance in process of treatment
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Linkosamides
Linkomycin Clindamycin
• Action spectrum: Gram positive aerobe cocci, grampositive and gramnegatvie anaerobes
• Penetrate all the tissues (don’t pass through HEB) including intracellurally
• Usage: usually in heavy infections, caused by anaerobe microorganisms
• A lot of side effects
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Linkomycini hydrochloridum
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Dalacyn C (clindamycini hydrochloridum)
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Tetracyclines
1. Natural - biosynthetic: chlortetracycline, oxytetracycline, tetracycline, dimethylchlortetracycline.
2. Semisynthetic:
doxycycline (vibramycin), metacycline (rondomycin), minocycline.
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Tetracycline
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Doxycycline
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Vibramycin (doxycycline)
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Shemes of tetracyclines administration
• Tetracycline - 0,25-0,5 g 4 times per 24 hours
• Methacycline – 0,3-0,6 g 2 times per 24 hours
• Doxycycline – 0,2 g (first day), 0,1g (next days) 1 time per 24 hours
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Pharmacokinetics of tetracyclines when combined with Pharmacokinetics of tetracyclines when combined with other drugsother drugs
Drugs Results of combined administration
Antacides (Ca+, Mg+ etc.)
Iron preparations
Rifampicin
Decrease of absorbtion
Decrease of absorbtion
Increase of elimination
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Side effects of tetracyclines• Dispeptic disorders, stomatitis, glositis,esophagitis,
pruritus etc). • Disbacteriosis and superinfection with Candida fungi,
proteus, pseudomonadas or staphylococci. • Photodermatosis. • Liver toxicity. • Absorbtion by bones and teeth of a featus or a child:
hipoplasia of dental enamel, disorder of teeth formation, tendency for caries.
• Antianabolic action, damage of kidneys (when using tetracyclines with long termed storage, using big doses).Tetracyclines are forbidden for children under the age of
8/12, during pregnancy, liver diseases, kidney insufficiency, miastenia
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Photosensitization - tetracyclines
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Tetracyclines
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AMINOGLYCOSIDES
• І generation: streptomycin, neomycin, monomycin, kanamycin
• ІІ generation: gentamycin (garamycin), tobramycin, syzomycin
• ІІІ generation: netilmycin (netromycin), amikacin.
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Gentamycin
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spectrum of action of aminoglycosides
wide• gram-negative bacteria (escherichia coli,
salmonella, klebsiella, especially K. рneumoniae, proteus, iersinia, brucella, campilobacteria, helicobacters, serratsia, shigella etc.).
• some gram-positive microorganisms, including staphylococci which are resistant to other antibiotics
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Indications for usage of aminoglycosides
- at the beginning stage of infectious processes of unknown ethiology and severe complexity (combined with beta-lactamase);
- considerable purulent-inflammatory component of heavy infections (peritonitis, sepsis, mediastinitis, abscesses and flegmones of soft tissues);
- acute attack of chronical purulent-inflammatory diseases, including secondary immune defficiency;
- early stage of development of secondary bacterial meningitis;- bacterial endocarditis;- infections of urinary tracts;- for prophilaxis of postoperative pustural complications
(combined with beta-lactamase antibiotics, metronidazole or other antianaerobe drugs);
- skin infections and subcutaneous fat tissue infections, burns.
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Concentration of aminoglycosides in blood should not overcome:
• Amikacin, kanamycin –
35-40 mkg/ml
• Gentamicin, tobramycin –
10-12 mkg/ml
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Complications in administration of aminoglycosides
• Ototoxicity • Nephrotoxicity • Neurotoxicity
According to extent of toxicitynetilmicin < gentamicin <tobramycin <
amikacin < neomycin < streptomycin < monomycin < kanamycin
• Leuko-, thrombocytopenia, hemmorhages, hemolisis
• Allergic reactions
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Chloramphenicol – levomycetin
Indications:
meningitis, typhoid fever, paratyphoid fever, brucellosis, tularemia
Side effects:• Hypochrome and aplastic anemia• Granulocytopenia, thrombocytopenia• «Grey syndrome of a featus»• Disbacteriosis and superinfection
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SUPER RESISTANT MICRO ORGANISMS (BUGS)
• MRSA- Methicilin resistant stapylococcus aureus
• VISA- vancomycin intermediate resistant staphylococci aureus
• ESBLS- Extended spectrum beta lactamase
• VRE- vancomycin resistant enterococci• penicillin resistant streptococcus
pneumonia
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DIAGNOSIS (CON’T)
• Determine cellulitis versus abscess
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PROPHYLAXIS (CON’T)
• Dental procedures recommended for prophylaxis
Updated JADA 2004
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DIAGNOSIS: Infection
• Determine etiology
> odontogenic
> trauma wound, animal bite
> TB, fungi, actinomycoses
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TREATMENT of INFECTION
• Remove the cause of infection is the most important of all, by either spontaneously or surgically drain the pus.
• Antibiotics are merely an adjunctive therapy.
Host defense
Drainage
Antibiotics
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SELECTION of A/B
• Use Empiric therapy routinely• Use the narrowest spectrum antibiotics• Use the antibiotics with the lowest toxicity
and side effects• Use bactericidal antibiotics if possible• Be aware of the cost of antibiotics
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• Empiric Antibiotics in OMF Infection
■ First-line
Penicillin 3MU IVA q6h -> Cefazolin 1000mg q6h
Gentamycin 60-80mg IVA q8h-q12h
■ Second line (3A) Augmentin 1200mg q8h + Amikin 375mg q12h +
Anegyn
■ Mild infection
Amoxicillin 250mg #2 PO q8h
Clindamycin 300mg PO q6h
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PROPHYLAXIS
• Indications
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PROPHYLAXIS (CON’T)
• Dental procedures recommended for prophylaxis
Updated JADA 2004
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ANTIFUNGAL AGENT
• Most of fungal infection are from candida• Commonly used drugs:
(1) Nystatin (Mycostatin)= PO 4-600,000 U qid
(2) Amphotericin B= IV for severe systemic infec.
(3) Fluconazole, Ketoconazole
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MOUTH RINSES
• 0.2% Chlorhexidine gluconate• Against G(+), G(-), fungus• Reduce pain and inflammation, enhance
healing• Indication: immunocompromised patient,
C/T R/T
(prophylaxis mouthrinse reduce oral mucositis)
• Use: 2-3 times daily,10-20cc/ time, 20-30sec.
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• Side Effect of Commonly Used Antibiotics
1. Penicillin hypersensitivity
2. Cephalosporin
hypersensitivity
3. Clindamycin diarrhea, pseudomembrane colitis
4. Aminoglycoside
damage to kidney, 8th neurotoxicity
5. Metronidazole*
GI disturbance, seizures
6. Vancomycin 8th neurotoxicity, thrombophlebitis
7. Chloramphenicol
bone marrow suppression
8. Erythromycin mild GI disturbance
9. Tetracyclin* tooth discoloration, photosensitivity
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• THANK -U