antibiotics and antibacterial drugs

ANTIBIOTICSANTIBIOTICSDr. V.RAMKUMAR

CONSULTANT DENTAL &FACIOMAXILOFACIAL SURGEON

REG. NO.4118. TAMILNADU- INDIA( ASIA)

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

Mechanism of the antibioticsMechanism of the antibiotics

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

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

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).

Nucleus of penicillin moleculeL – beta-lactame ring, T – thiazoline ring

N

TL

S

CO

OH

CH3

CH3

O

H2N

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

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

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

OxacillinOxacillin 

Antistaphylococci penicillinase-resistant semisynthetic penicillin, acid stable

 Administration: intramuscular, intravenously, oraly 3-6-8 g/24 hours (4-6 times of injections)

.

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

Ampicillin

Amoxicillin

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

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

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)

Inhibitors of beta-lactamases 

Clavulanic acid Sulbactam

Tazobactam 

Unasyn (ampicillin/sulbactam)

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

Structure of cephalosporinsL – beta-lactame ring, D – dihydrothiazine ring

CH2 O CO CH3

C

O

H2N

O

OH

S

L D

N

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 * -

Cefazolin-sodium (C I)

Cezolin (Cefazolin, C I)

Cefalexin ( C I)

Zinnat (Cefuroxime, C II)

Cefotaxime (C III)

Claphoran (cefotaxime, C III)

Cefobid (Cefoperazone, C III)

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 ++ +++ ++ ++

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) 

Cephalosporines Cephalosporines

NNot recommendedot recommended to combine with other nephrotoxic drugs

(aminoglycosides)

ContraindicatedContraindicated to combine with loop diuretics (furosemid,

etacrinic acid) 

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).

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

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

Erythromycin

Macropen (midecamycin)

Sumamed (azithromycin)

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.)

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

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

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

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

Linkomycini hydrochloridum

Dalacyn C (clindamycini hydrochloridum)

Tetracyclines

1. Natural - biosynthetic: chlortetracycline, oxytetracycline, tetracycline, dimethylchlortetracycline.

2. Semisynthetic:

doxycycline (vibramycin), metacycline (rondomycin), minocycline.

Tetracycline

Doxycycline

Vibramycin (doxycycline)

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

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

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

Photosensitization - tetracyclines

Tetracyclines

AMINOGLYCOSIDES

• І generation: streptomycin, neomycin, monomycin, kanamycin

• ІІ generation: gentamycin (garamycin), tobramycin, syzomycin

• ІІІ generation: netilmycin (netromycin), amikacin.

Gentamycin

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

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.

Concentration of aminoglycosides in blood should not overcome:

• Amikacin, kanamycin –

35-40 mkg/ml

• Gentamicin, tobramycin –

10-12 mkg/ml

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

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

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

DIAGNOSIS (CON’T)

• Determine cellulitis versus abscess

PROPHYLAXIS (CON’T)

• Dental procedures recommended for prophylaxis

Updated JADA 2004

DIAGNOSIS: Infection

• Determine etiology

> odontogenic

> trauma wound, animal bite

> TB, fungi, actinomycoses

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

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

• 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

PROPHYLAXIS

• Indications

PROPHYLAXIS (CON’T)

• Dental procedures recommended for prophylaxis

Updated JADA 2004

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

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.

• 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

• THANK -U