“Antibiotics part I”

Kharkiv National Medical University

Department of Pharmacology and Medical Prescription

assistant Gordiychuk D.

Plan of lecture: Principles of antibiotictherapy. Pharmacology of Penicillins, Cephalosporines,

Carbapenems and Monobactams.

Antibiotics

Antibiotics and vaccines are among the biggest medical advances since 1000. (Culver Pictures)

Antibiotics ("Anti" – against, "bios" - life)

Antibiotics - a substance produced by microorganisms, or produced from vegetable and animal tissues, and their semi-synthetic and synthetic analogs selectively inhibit the viability of microorganisms sensitive to them.

Importance of Antibiotics: The elimination of the global crisis of infectious diseases (cholera, plague,

dysentery). Effective at the dangerous diseases (sepsis, meningitis, peritonitis,

pneumonia). ≈ 20 million people die each year from infectious diseases. 1/3 of all hospital patients are treated with antibiotics. Over the past 20 years there were 20 new infectious diseases

(Legionnaires' disease, hairycell leukemia, hemorrhagic fever and others). Unconventional use of antibiotics: peptic ulcer, asthma, myocardial

infarction, atherosclerosis. In breadth of application group of antibiotics ranked the first place in the

world. Today, there is no person at least who did not use antibiotics. There is no country that doesn’t threat of epidemics and pandemics.

Antibiotics could be

narrow-spectrum and effective only against a limited variety of pathogens or broad-spectrum, affecting many different types of pathogens

bactericidal if they kill the susceptible bacteria or bacteriostatic if they inhibit the growth of bacteria

Classification of antibiotics.I. Β-lactamsI. Β-lactams1.1. PenicillinPenicillinss::

NNatural atural

SSemi-syntheticemi-synthetic

AntistaphylococcalAntistaphylococcal

AminopenicillinsAminopenicillins

AntipseudomonaAntipseudomona

CCombinedombined

2. 2. CephalosporinsCephalosporins

3. 3. CCarbapenem and arbapenem and monobactamsmonobactams

II. GlycopeptideII. Glycopeptidess

III. Macrolides and III. Macrolides and AAzalideszalides

IV. TetracyclineIV. Tetracycline

V.AminoglycosidesV.Aminoglycosides

VI. PolymyxinVI. Polymyxinss

VII. VII. GGramicidinramicidin

VII. VII. CCycloserineycloserine

IX. AntifungalIX. Antifungal

X. LincosamidesX. Lincosamides

XI.XI.CChloramphenicolhloramphenicol

XII. XII. FFuzidinuzidin

1928 - Scottish microbiologist A. Fleming discovered penicillin - P. notatum.

1940 - British W. Florey and Chain received penicillin E.

In 1945, Fleming, Florey, Chain received the Nobel Prize for the discovery of penicillin.

1942 - Z. Yermolyeva - Penicillin crustosum. 1944 - American Z. Waxman – streptomycin. 1960-1980 - cyclosporine, rifampicin, semisynthetic

penicillins, tetracyclines, macrolides, azalides. Today ≈ 6 thousand antibiotics. But, 2-3% of them are

use (300 INN ≈ 2000 oficinal names). ~ recent year: modifying old drugs, finding new discipline

in antibacterial combats.

A brief history of antibiotics

Requirements for Antibiotic

high selectivity lack of toxicity long-term providing of therapeutic

concentrations lack of rapid resistance development availability of suitable dosage forms

Classification according SPECTRUM OF ACTION.

Narrow spectrum (mainly Gr + and Gr-): Natural, antistaph. penicillins Cephalosporins I generation, monobactams Polimyxins, gramicidin C Fuzidin Antifungal Broad-spectrum: Semi-synthetic penicillins and cephalosporins II -IV Carbapenems, Tetracyclines, Macrolides,

Aminoglycosides Chloramphenicol

Antimicrobial drugs have also beenclassified broadly into:

1. bacteriostatic, i.e. those that act primarily by arresting bacterial multiplication, such astetracyclines, chloramphenicol, macrolides,lincosamides.

2. bacteriocidal, i.e. those which act primarilyby killing bacteria, such as penicillins,cephalosporins, aminoglycosides, isoniazid,rifampicin, quinolones etc.

Classification according MECHANISM OF ACTION

INHIBIT:

the synthesis of the components of microbial wall

the function of the cytoplasmic

membrane

the synthesis of proteines

β- LACTAMS POLIMYXINES MACROLIDES*

AZALIDES

LINCOSAMIDES*

RIFAMYCINS

FUZIDIN

CHLORAM-PHENICOLES*

GLYCOPEPTIDES GRAMICIDINE TETRACYCLINES*

PHOSPHOMYCINE

CYCLOSERINEANTIFUNGAL AMYNOGLY-

COSIDES

Has bactericidal and bacteriostatic* effect

Bacterial cellBacterial cell

Cell wall

Nuclear apparatus

Cytoplasmic membrane

Ribosomes

Violation of the cell wall

synthesis.

Violation of cytoplasmic

membranes permeability.

Violation of RNA

synthesis

Violation of protein

synthesis at the level of

ribosomes.

B-lactamsGlycopeptide

PolymyxinsGramicidinAntifungal

Rifampicin

TetracyclinesChloramphenicolsLincosamidesMacrolidesAzalidesAminoglycosidesFuzidinum

Negative effects of Antibiotics:1.The emergence of sustainability:   production of beta-lactamase;   changes in the permeability of the cytoplasmic membrane;   changes in the structure of certain portions of ribosomes

proteins or enzymes2.  Superinfection;3. Dysbiosis;4. Allergic reactions;5. Systemic toxicity, nephrotoxicity, hepatotoxicity. Penicillins are the least toxic!!!

•Antimicrobial therapy and pregnancy

•Azithromycine•Erythromycine•Penicillins•The most of cefalosporines

Conditions for rational use of antibiotics Antibiotics should be given according to antibiogram. Choose the most active and least toxic antibiotic. To determine the optimal antibiotic dose and route of

administration based on the its pharmacokinetic and the concomitant disease. The concentration of antibiotic in the blood should be 3-4 times bigger in comparison with minimum inhibitory concentration for the selected pathogen.

Apply the first striking dose, followed by supporting. To determine the tolerance of antibiotics in patients according

to the basis of medical history. To take in account an adverse effects of antibiotics,

especially in the liver and/or kidney failure. Early antibiotic treatment till consolidation of therapeutic

effect. Consideration of cross sensitivity. Use a combination of antibiotics in order to expand and

strengthen the action of the antibacterial effect. Use of antifungal drugs to prevent dysbiosis.

BETA-LACTAM ANTIBIOTICS(inhibitors of cell wall synthesis)

Their structure contains a beta-lactam ring.

The major subdivisions are:

(a) penicillins whose official names usually include or end in “cillin”(b) cephalosporins which are recognized by the inclusion of “cef” or “ceph” in their official names. (c) carbapenems (e.g. meropenem, imipenem)(d) monobactams (e.g. aztreonam)(e) beta-lactamase inhibitors (e.g. clavulanic acid, sulbactam).

β-lactams Mechanism of Action

Action target: cell wall on penicillin binding proteins (PBPs) Transpeptidases (form cross-links in peptidoglycan) Beta-lactam ring attached to 5-membered

thiazolidine ring Accessibility of PBPs differ in gram+ and gram-

bacteria. Amino acyl side chain groups determine spectrum,

adsorption, susceptibility to lactamase. Bactericidal inhibitors.

Penicillin

Classification of penicillins

1.Natural penicillins: a) Short acting: Penicillin-G Penicillin-sodium Penicillin-potassium Penicillin V b) Long acting: Penicillin G. procaine Benzathine penicillin (Bicillin-I) Bicillin-3,-5

2. Semisynthetic penicillins: I. Penicillinase resistant Oxacillin Dicloxacillin Cloxacillin Methicillin II. Broad spectrum penicillins Aminopenicillins Ampicillin Amoxicillin Pivampicillin Talampicillin

Classification of penicillins

III. Carboxypenicillins Carbenicillin Ticarcillin IV. Ureidopenicillins Azlocillin Piperacillin V. Combined penicillins Unazin Ampiox (Ampicillin+Oxacillin) Augmentin (Amoxycillin+Clavulanic acid) Magnapen (Ampicillin+Flucloxacillin)

Classification of penicillins

Spectrum of natural penicillins Gr+ microorganisms include: staphylococci, streptococci (pneumoniae, pyogenes and

viridans group), bacillus anthracis, clostridium perfringens, corynebacteria diphtheriae and listeria

monocytogenes

Spectrum of natural penicillins (cont.)

Sensitive Gr- microorganisms include: Neisseria gonorrhoeae, Neisseria meningitis, Leptotrichia buccalis, Treponema pallidum, Treponema partenue.

Pharmacokinetics of natural penicillins

1. Acidic instability (exception Penicillin V) 2. Extracellular distribution mainly 3. Poor penetration through BBB 4. Crossing the placenta 5. Protein binding 60% 6. Small amount metabolizing 7. Excretion mainly by tubular secretion. It

may be suppressed by probenecid (uricosuric)

Clinical uses of natural penicillins Endocarditis Pericarditis Meningitis Pneumonia Septicemia caused by streptococcus pyogenes Gonorrhea Syphillis (congenital and neurosyphillis).

Clinical uses of natural penicillins(cont.)

Anthrax, Actinomycosis (abdominal, cervicofacial or

thoracic disease), Botulism, Gas gangrene, Tetanus, Diphtheria (prevention of carrier state), Empyema, Rheumatic fever, Listeriosis.

Side effects of natural penicillins Penicillin G (benzyl penicillin) is one of the least

toxic antibiotics. It does not cause any direct toxicity. Only in very high doses, especially injected IV, it can cause neurotoxic effect and bleeding.

The hypersensitivity reactions are the major problem, incidence up to 10%.

Semisynthetic penicillinsI. Penicillinase resistant: Oxacillin, Dicloxacillin, Cloxacillin,

Methicillin The advantages of penicillinase resistant

semisynthetic penicillins over natural ones are in efficacy against penicillinase producing staphylococci and stability of some of them (Oxacillin) in acidic medium.

They are used in treatment of infection caused by staphylococci resistant to penicillins.

Semisynthetic penicillins II. BROAD SPECTRUM PENICILLINS a) Aminopenicillins

The aminopenicillins have identical spectrum and activity, but amoxicillin is better absorbed orally (70–90%). They are effective against: streptococci, enterococci Gram-negative organisms (including H. pylori) but have variable activity against staphylococci ineffective against P. aeruginosa.

Amoxycillin and Ampicillin

•Carboxypenicillins- Carbenicillin- Ticarcillin

•Ureidopenicillins- Azlocillin- Mezlocillin- Piperacillin

b) Antipseudomonal penicillinsThese drugs retain activity against streptococci andpossess additional effects against Gr-organisms, including various Enterobacteriaceaeand Pseudomonas.

There is cross-allergy between all the variousforms of penicillin, probably due in part to theircommon structure, and in part to the degradationproducts common to them all. Partial cross-allergy exists between penicillinsand cephalosporins (a maximum of 10%) which is of particular concern when the reaction to eithergroup of antimicrobials has been angioedema or anaphylactic shock. Carbapenems and the monobactams apparently have a much lower risk of cross-reactivity.

Adverse effects

Thrombophlebitis

Allergic reactions

Superinfections (diarrhea)

Seizures (rare)

Stevens – Johnsonsyndrome

Lyell syndrome

Resistance

B-lactamaseTypes:

Different substrate specificity Penicillinases Cephalosporinases

Location: Gram+: extracellularly Gram-: periplasmic space

Failure to bind to PBPs Cannot penetrate porins (gram-) Production of lactamase (penicillinase) Lack autolytic enzyme

Policy to deal drug resistance Ideally, bacteriological management of

clinical infection should involve:

1. Identification of causative organism2. Sensitivity test3. Follow-up the drug effect4. Monitor antibiotic level to avoid toxicity.

In reality, most patients requiring antimicrobial therapy are treated empirically. In serious infections immediate chemotherapy may be life-saving.

CEPHALOSPORINS

Cephalosporins have 7-aminocephalosporanic acid nucleus.

Cephalosporins are produced semisynthetically from cephalosporin- C obtained from a fungus Cephalosporium.

Spectrum – broad Mechanism - inhibition of synthesis of bacterial

cell wall. Effect - bactericidal

1.FIRST GENERATION Cephalosporins of the first generation are highly active against

Gram+ but weaker against Gram- microorganisms.

I.Cefazolin

II.Cefalexin 2. SECOND GENERATION The drugs were developed subsequently to the first generation;

they are more active against Gram-negative microorganisms.

III.Cefuroxim

IV.Cefaklor

5 generations of CEPHALOSPORINS

3. THIRD GENERATION They have enhanced activity against gram-negative bacilli,

including most enteric organisms and Serratia marcescens. Ceftriaxone and cefatoxime have become agents of choice in the treatment of meningitis.

Ceftazidime has activity against Pseudomonas aeruginosa.

V.Ceftriaxone VI.Cefixime VII.Cefoperazone VIII.Ceftazidime IX.Cefatoxime

5 generations of CEPHALOSPORINS (cont.)

4. 4-th generation These drugs are in many ways similar to

cephalosporins of 3rd generation X. Cefepim XI.Cefpirom 5. 5-th generation XII.Ceftobiprole XIII. Ceftaroline Antimicrobial activity: Ceftobiprole has powerful

antipseudomonal effect and is less susceptible to development of resistance. Ceftaroline does not have an anti-pseudomonal activity.

5 generations of CEPHALOSPORINS (cont.)

CEPHALOSPORINS

Type of action: bactericidal = penicillins Spectrum: WIDE

INDICATIONS infectious diseases of the respiratory, urinary and

biliary tract, abdominal cavity, skin, bones, joints, heart,

Gonorrhea, burns, surgical prophylaxis, Meningitis and Pseudomonas infection - III -IV

generation. Side effects: hemorrhage, hemato-, nephro-, neuro-,

hepatotoxicity. Contraindications: porphyria, epilepsy, severe liver

and kidney diseases, pregnancy, lactation.

Sulperazon - "protected" (Cefoperazone + Sulbactam)

Spectrum: wide G+, Gr-, anaerobes Resistant to β-lactamases of extended

spectrum (sulperazon and carbapenems) Application: for severe community-acquired

and hospital-acquired infective processes: primary and secondary peritonitis, infected pancreatic necrosis, sepsis, diabetic foot, phlegmons, nosocomial pneumonia.

Comparison activity of CEPHALOSPORINS.

GenerationGeneration

ActivityActivity

Gr+Gr+ Gr-Gr-

1-st1-st ++++++ +/-+/-

2-st2-st++++ ++

3-st3-st++ ++++++

4-st4-st ++++ ++++++

Pharmacological "face" of CEFALOSPORINES

Similar to penicillin in structure and action. Wide spectrum. Powerful bactericidal effect. Low toxicity. Good compatibility with other antibacterial

agents. Most resistant to staphylococcal β-lactamase. Cross allergic to penicillin. It penetrates into the tissue fluid, joints, bones. Good compatibility with other antibacterials.

CARBAPENEMS and MONOBACTAMS CARBAPENEMSCARBAPENEMS MONOBACTAMSMONOBACTAMS

1. 1. IMIPENEMIMIPENEM--CILASTATINECILASTATINE

2. 2. MEROPINEMMEROPINEM**

3. 3. AZTREONAMAZTREONAM

MECHANISM:MECHANISM: inhibit the PBPs (transpeptidase), Imipenem - PBPs-2. inhibit the PBPs (transpeptidase), Imipenem - PBPs-2.

SPECTRUMSPECTRUM

ultra-wide:ultra-wide: the majority of aerobic the majority of aerobic and anaerobic Gr+ and Gr- resistant and anaerobic Gr+ and Gr- resistant bacteria; 80% of strains of bacteria; 80% of strains of Pseudomonas aeruginosa, Pseudomonas aeruginosa, postantibiotic effect (Gr-).postantibiotic effect (Gr-).

narrow:narrow: GrGr-- aerobes: gono-, aerobes: gono-, meningococcus, Salmonella, Shigella, meningococcus, Salmonella, Shigella, Klebsiella, Klebsiella, ProteusProteus and Escherichia and Escherichia colicoli, , Pseudomonas etc.Pseudomonas etc.

INDICATIONSINDICATIONS

severe infections of bones and joints, severe infections of bones and joints, skin and soft tissue, abdominal, skin and soft tissue, abdominal, female genitals, urinary tract female genitals, urinary tract infections, pneumonia, septicemia, infections, pneumonia, septicemia, meningitis.meningitis.

severe infections caused by Grsevere infections caused by Gr-- flora flora resistant to III generation resistant to III generation cephalosporins, aminoglycosides II-III cephalosporins, aminoglycosides II-III generationgeneration,, pseudomonas penicillin pseudomonas penicillinss..

- resistant to -lactamases, * - resistant to renal dehydropeptidase

Pharmacological «face» of CARBAPENEMS and MONOBACTAMS

CARBAPENEMS MONOBACTAMS Ultra-wide spectrum,

including strains resistant to cephalosporins III and IV generation.

Potent resistance to β-lactamase.

Potent postantibiotical effect. Slow development of

resistance. Antibiotics of ultradeep

reserve! Low toxicity and good

tolerability.

The narrow spectrum of action (aerobic Gr-), identical to cephalosporins III.

Potent resistance to Gr-

β-lactamase. Potent bactetiocidal action. Slow development of

resistance. No cross-sensitization to

penicillins and cephalosporins. The use in newborns. Antibiotics of reserve!

Side effects of MONOBACTAMS AND CARBAPENEMS

CARBAPENEMS CRAMPS, WEAKNESS, TREMOR, ENCEPHALOPATHY, HYPOTENSION, NAUSEA, VOMITING, SUPERINFECTION, PSEUDOMEMBRANOUS

COLITIS, PHLEBITIS, THROMBOCYTOSIS, EOSINOPHILIA.

MONOBACTAMSAllergic reactions: URTICARIA, PRURITUS, ERYTHEMA, EOSINOPHILIA, ARTHRALGIA, VASCULITIS, ANGIOEDEMA, BRONCHOCONSTRICTION, ANAPHYLAXIS.