Antibiotics

Antimicrobial drugs

Antimicrobial drugs

Antibiotics Synthetics

Antibiotic: Chemical produced by a microorganism that kills or inhibits the growth of another microorganism

Synthetic antimicrobial agent: Chemical that kills or inhibits the growth of microorganisms

Definition of AntibioticA substance of biological, semisynthetic (orsynthetic) origin of low molecular weight producedby a fungus or bacterium as secondary metabolitesthat inhibits or stop growth of other microorganismsin vitro and in vivo selectively, when it used in lowconcentration

Literal translation: anti – against, biotic – livingthings

Antibiotics cause greater harm to microorganismsthan to human host

Discovery of antibiotics

Alexander Fleming discovered penicillin while working with Staphylococcus. Noticed there were no Staph colonies growing near a mold contaminant. Identified mold as Penicillium and was producing a bactericidal substance that was effective against a wide range of microbes. But Fleming was unable to purify compound.Ernst Chain and Howard Florey successfully purified penicillinIn 1941 tested on human subject with life threaten Staphylococcus

aureus infection

Selman Waksman isolated streptomycin from soil bacterium Streptomyces

griseus

History and Development ofAntimicrobial Drugs

Antimicrobial action:

1. bacteriocidal - Kill bacteria2. bacteriostatic - Reversibly inhibit growth

Spectrum of activity:

1. Narrow spectrum: Gram positive only OR Gram negative only

2. Broad spectrum: Gram positive AND Gram negative(Disadvantage of broad spectrum is disruption of normal

flora)

Features of Antimicrobial Drugs

1. Diagnosis?

- Accurate history, physical exam, imaging, labs

-Microbiological tests

- Differential diagnosis

2. Host?

- Age

-Immunity

- Renal and liver function

- Allergies

- Pregnancy, breastfeeding

- Genetics

Principles of antibacterial therapy

3. Treatment strategy?

Which antibacterial drug?

- Empiric therapy ( treatment of an infection beforespecific culture information has been reported orobtained) in severe infections

- Definitive therapy

- Prophylaxis (treatment with antibiotics to prevent aninfection, as in intra-abdominal surgery)

Which route? Duration? Minimum duration 5 days (andthe patient has been afebrile for at least 3 days)

4. Observation (temperature, functons of kidneys and liver and other)

Principles of antibacterial therapy

Effects of combinations of antimicrobial drugs

Combination some times used to treat infections

When action of one drug enhances another, effect is synergistic

When action of one drug interferes with another, effect is antagonistic

When effect of combination is neither synergistic or antagonistic, effect said to be additive

Adverse effects

⚫ Allergic reactions⚫ Irritant effect on the ways of administration (i.v. - phlebitis,

i.m. - infiltration, orally - diarrhea)• Toxic effects• Disbacteriosis (Overuse of antibiotics can damage our normal/good bacteria. Many antibiotics prescribed by the doctor kill the good bacteria as well as the bad. With the good bacteria gone there is more room for bad microbes to invade!)• Formation of the drug resistance

Antimicrobial drug resistance

The acquired ability of a microorganism to resist

the effects of a chemotherapeutic agent to

which it is normally sensitive

Means that the bacteria survive and continue to multiply after administration of the antibiotic

Agriculture

Inpatient

Outpatient

Antibiotic Use Leads to Antibiotic Resistance

Factors promoting drug resistance Exposure to sub-optimal levels of antimicrobial

Exposure to microbes carrying resistance genes

Inappropriate drug use-

Lack of quality control in manufacture or outdated antimicrobial

Inadequate surveillance or defective susceptibility assays

Poverty or war

Use of antibiotics in foods-Antibiotics are used in animal feeds and sprayed on plants to prevent infection and promote growth

13

Antimicrobial Drug Resistance

• Resistance can be minimized by using antibiotics

correctly and only when needed

• Resistance to a certain antibiotic can be lost if

antibiotic is not used for several years

De-escalation of therapy

Once micro results are available, therapy can be targeted at the causative organism based on its antibiotic susceptibilities

May mean switching to a more narrow-spectrum antibiotic, which reduces negative effects on the body’s natural flora

15

Acquisition of resistance- Can be due to spontaneous mutation(vertical evolution)- Or acquisition of new genes:* horizontal transfer* Plasmid mediated

Antimicrobial Drug Resistance

Mechanisms Of Antibiotic Resistance

• Bacteria are capable of becoming resistant through several mechanisms

• One or many mechanisms may exist in an organism

• Multidrug-resistant bacteria often have multiple mechanisms

• Genes encoding resistance may exist on plasmid or chromosome

• Enzymatic destruction of

drug

• Prevention of penetration

of drug

• Alteration of antibiotic or

target site

• Rapid ejection of the drug

Mechanisms Of Antibiotic Resistance

Mechanisms of ResistanceAntibiotic Degrading Enzymes

β-lactamases

Simple, extended spectrum β-lactamases (ESBL), cephalosporinases, carbapenemases

Confer resistance to some, many, or all beta-lactam antibiotics

Chloramphenicol acetyltransferase-inactivates the drug by 3-o-acetylation

Erythromycin esterase - seen in E.coli-hydrolyze lactone ring thus deactivating it - limits utility of oral erythromycin

Resistance to Antibiotics

Mechanisms of Resistance

Decreased uptake of the drug (Altered influx)

Mutation in a transporter (alterations in porin proteins) necessary to import antibiotic can lead to resistance (Carbapenems).

Increased elimination of the drug (Altered efflux)

Acquire transporter gene that will pump the antibiotic out (efflux pumps) - Tetracycline resistance

Mechanisms of Resistance

Alteration of target molecule (Mutation in the target site)

Minor structural changes in antibiotic target can prevent binding

- Changes in ribosomal RNA prevent macrolids from binding to ribosomal subunits - Alteration of ribosomal target sites-hence

failure to inhibit protein synthesis and cell growth.

- Penicillin binding proteins (penicillins) - MRSA

- RNA polymerase (rifampin)

- 30S ribosome (streptomycin)

Mechanisms of Resistance

Fig 20.20

Classification Abs by mechanism of actionBactericidal:

Inhibition of cell wall synthesis

1.β-lactam antibiotics:

penicillins

cephalosporins

carbapenems

2. Glycopeptides

3. Fosfomycin

Inhibition of protein synthesis

1. Aminoglycosides

Inhibition of cytoplasmic membrane

1. Lipopeptides

2. Polymyxins

Classification by mechanism of actionBacteriostatic:

Inhibition of protein synthesis

1. Macrolides

2. Tetracyclines

3. Chloramphenicol

4. Lincosamides

5. Oxazolidinones

6. Glycylcyclines

Injury the synthesis of RNA in a bacterial cell

1. Ansamycins

Bactericidal antibiotics

Inhibition the synthesis of cell walls

-lactam antibiotics

ClassificationPenicillins Cephalosporins

Natural

Benzylpenicillin Na-salt;

Benzathine benzylpenicillin

I generation

Cefazolinum;

Cefalexin (per os)

β-lactamase-resistant penicillins

Oxacillin

II generation

Cefuroxime;

Cefuroxime axetil (per os)

Aminopenicillins

Amoxicillin;

Ampicillin

III generation

Cefotaxime; Cefoperazone;

Cefixim (per os)

Antipseudomonal penicillins

Piperacillin

IV generation

Cefepime

Penicillin-beta-lactamase inhibitor combination drugs Amoxicillin/clavulanate;

Piperacillin/tazobactam

V generation

Ceftaroline

Cephalosporin-beta-lactamase inhibitor combination drugs

Cefoperazone/sulbactam

carbapenems

Imipenem;

Meropenem

The structure of the cell walls of bacteria

A-Gram" +»

B-Gram «-»

The composition of the cell wall includes a special peptidoglycan-murein. Peptidoglycan fibers are very long and are fastened together by a set of cross-sections. Monomers are molecules formed by aminosaccharides and Penta peptide L-Ala-D-Glu-L-Lys-D-Ala-d-Ala.

β-lactam AB penetrate peptidoglycan and bind with "penicillin binding proteins" → the formation of an inhibitory complex, which:

1. inhibits the transpeptidase reaction → as result the formation of cross-linking between molecules of peptidoglycans is disturbed,

2. activates autolytic enzymes in the cell wall → a partial destruction of peptidoglycans,

Inhibition and lysis of the cell wall.

Bactericidal action.

Low toxicity.

Excretion by the kidneys.

Wide range of dosages.

Cross allergy between penicillins, cephalosporins and carbapenems

1. PenicillinsGeneral property

Natural penicillinsPenicillin G (benzylpenicillin)

Pharmacokinetics: Acid resistance → parenteral route: i.v, i.m., epidural T1 / 2 3-4 hours → take 6-8 times a day;It is excreted unchanged by the kidneysSpectrum of activity narrow (mostly Gr "+»):Streptococcus and pneumococcus (skin and soft tissue infections, sore throat, outpatient pneumonia);Corinebacteria diphtheria (diphtheria)Spore-forming anaerobes: clostridia, anthrax Bacillus (tetanus, gas gangrene, anthrax);Meningococc (meningitis);

Pale Treponema (syphilis)

NO effect ON GONOCOCCI AND STAPHYLOCOCCI (produce β-lactamase)

Long duration of action (action 7-14 days).

Taken only i.m.

Indications: treatment of streptococcal infections (erysipelatous inflammation, prevention of attack of rheumatism) and syphilis.

Natural penicillinsBenzathine benzylpenicillin

(bicillin-1 )

Oxacillin,

The spectrum: as natural penicillins + staphylococci, producing β-lactamases (resistant to penicillin, aminopenicillins, anti-Pseudomonas penicillins).

Route of administration: i.m., i.v., per os

Indications: infections of the skin, soft tissues, bones and joints, pneumonia, endocarditis, meningitis, sepsis.

β-lactamase-resistant penicillins (antistaphylococcal)

Methicillin is a isoxazolylpenicillins. It is not used now.

In the case of MRSA-infection penicillins, cephalosporins and carbapenems not used.

Methicillin-resistant Staphylococcus (MRSA)

➢ Ampicillin➢ AmoxicillinDegraded by β-lactamases.Acid-resistant.A Broad spectrum of action: G + cocci: pneumococci,

enterococci, Neisseria, Treponema, Gr " - " intestinal group (Escherichia coli, Shigella,

Salmonella); hemophilic bacteria, Spore-forming bacteria: clostridia, anthrax Bacillus; H. pylori (amoxicillin), Listeria, Bordetella

Aminopenicillins

Ampicillin Amoxicillin

More active Shigella (Sonnei) Pneumococcus', H. pylori

Route of administration

i.v., i.m., per os per os

Bioavailability 40% 95%

Level in sputum Low, unstable High, stable

Adverse reaction Diarrhea (often)Skin allergic reactions (often)Ampicillin rash

Diarrhea (rare)Skin allergic reactionsAmpicillin rash

Comparative characteristics of ampicillin and amoxicillin

Compounds, inactivating β-lactamases:

clavulanic acid (clavulanate), sulbactam

and tazobactam.

Combination penicillins:

Amoxicillin/clavulanate;

Ampicillin / sulbactam;

Ticarcillin / clavulanate;

Piperacillin / tazobactam

Penicillin-beta-lactamase inhibitor combination drugs

Taken orally and i.v. every 8 hsIt is excreted by kidney and GIT.Spectrum of action: Gr ( + ) cocci: staph (including penicillin-resistant S. aureus and S. epidermidis), Streptococcus, Enterococcus;

Gr ( - ) bacillus: N. influenzae, M. catarrhalis, N.

gonorrhoeae, E. coli, Proteus spp., Klebsiella spp. etc., (including β-lactamase-producing );Anaerobic bacteria: spore - and asporogenous.Indications: sinusitis, otitis, bronchitis, pneumonia;acute cholecystitis, cholangitis, intraabdominal infections;acute pyelonephritis, cystitis, gynecological infections;infections of the skin, soft tissues, bones and joints, sepsis

Amoxicillin/clavulanate

This group consists of two subgroups: carboxypenicillins (ticarcillin)ureidopenicillins (piperacillin).

Piperacillin is mainly used .

Active against P. aeruginosa, as well as some ampicillin-resistant gram-negative bacteria (Enterobacter, Proteus, Morganella).

Used: Pseudomonas aeruginosa infection in combination with aminoglycosides II-III generation or ciprofloxacin.Route of administration: i.v. every 6-8 hs

Anti-Pseudomonas penicillins

Allergic reaction,

Diarrhea (ampicillin, amoxicillin),

Maculopapular rashes (not allergy, but usually if a patient has mononucleosis and takes ampicillin or amoxicillin),

Neurotoxicity (high doses of penicillin)

Side effects

Bactericidal action.

Broad spectrum.

Cross allergy with penicillin.

No effect on enterococci, Listeria, MRSA.

They are destroyed by β-lactamases.

Synergism with aminoglycosides.

2. CephalosporinsGeneral property

➢Cefazolinum

➢Cefalexin (per os)

Spectrum of action: narrow, mainly Streptococcus and Staphylococcus

Indications:

For Cefazolin: perioperative prevention;

For Cefalexin: Streptococcus. tonsillopharyngitis

For both: skin and soft tissue infections

I generation cephalosporins

➢Cefuroxime➢Cefuroxime axetil (per os)

Spectrum: broad, same I generation + H.influenzae, M. catarrhalis, E. coli, some strains of Klebsiella andProteus.

Indications: Acute otitis media (except Cefaclor), acute sinusitis,

bronchitis, pneumonia;Pyelonephritis;Infections of the skin, soft tissues, bones and joints.Perioperative antibiotic prophylaxis.

II generation cephalosporins

Spectrum: broad, same generation II + enterobacteria + meningo and gonococci + Pseudomonas aeruginosa (ceftazidime, cefoperazone)

BUT! Antistaphylococcal activity is less than that of first generation

Indications: severe infectionsUpper and lower respiratory tract, including nosocomial infections, biliary and urinary tract, bone, joint, skin and soft tissue, intra-abdominal and pelvic infections (in combination antianaerobic agent with drugs), shigellosis, salmonellosis, Bacterial meningitis.Sepsis.Gonorrhea

III generation cephalosporins

Parenteral Oral

Cefotaxime

Cefoperazone

Cefixime

Cefoperazone/sulbactam

Pharmacokinetics, adverse reactions are similar tocefoperazone, but more active against G «-» bacteria wichsynthesize β-lactamase - Enterobacteriaceae, Acinetobacter +effect on B. fragilis and other anaerobes nonspore

in abdomen and pelvis infections can be used asmonotherapy.

Cephalosporin-beta-lactamase inhibitor combination drugs

➢Cefepime

Spectrum: same III generation (including strains synthesizing β-lactamases class AMRs-nosocomial Enterobacter and Citrobacter strains) + Pseudomonas aeruginosa.

Indications:Severe nosocomial infections caused by multiresistant

bacteria (pneumonia, urinary tract infections, intraabdominal and pelvic infections, skin infections, soft tissue infections, bone and joint infections), sepsis, neutropenic fever.

IV generation cephalosporins

➢Ceftaroline is an active metabolite of ceftaroline fosamil.

Spectrum: same III-IV generation, including Str.pneumoniae resistant to penicillins, cephalosporins, macrolides and fluoroquinolones, + H. Influenzae, producing β-lactamases + MRSA.

Indications: complicated skin and soft tissue infections, community-acquired pneumonia caused by MRSA, Str. pneumoniae, H. influenzae, H. parainfluenzae, K. pneumoniae, and E. coli.

V generation cephalosporins

Allergy (cross with penicillins);

Irritation at the injection site: phlebitis and infiltration;

Diarrhea (in cephalosporins excreted in bile);

Leukopenia (rarely);

Nephrotoxicity (in the presence of kidney diseases)

Hypoprothrombinemia (cefoperazone);

Disulfiram-like effect (cefoperazone).

Side effects

➢ Imipenem/cilastatin (inhibitor of renal dehydropeptidase I)➢ Meropenem

Spectrum: broad, same cephalosporins III-IV, including resistant strains producing β-lactamases, + P. aeruginosa + nonsporous anaerobes.

Indications: severe infections caused by multiresistant or mixed flora: nosocomial pneumonia, complicated bone and soft tissue infections, intraabdominal and pelvic infections, pyelonephritis, sepsis, neutropenic fever, Pseudomonas infection + meningitis caused by Gr " - " bacteria (Meropenem)

3. CarbapenemsGeneral property

Allergic reactions (rarely cross Allergy with penicillins);

Dyspepsia;

Imipenem - convulsions (due to competitive antagonism with GABA)

Side effects

Glycopeptides

➢ VancomycinMechanism of action: block the synthesis of the cell wall of

bacteria by irreversible binding to the end portion of the amino acid bridge involved in the formation of cross-links between polysaccharide chains D-Ala-d-Ala.

Spectrum: narrow, Gr " + " aerobic and anaerobic: Staphylococcus (including MRSE, MRSA), Streptococcus, pneumococcus, Enterococcus, Peptostreptococcus, Listeria, corynebacteria, Clostridium (including C. difficult).

Glycopeptides are inactive against almost all Gr "-", since their large molecule is not able to penetrate the outer membrane of bacteria.

Indications: in case of allergy or resistance to β-lactam antibiotics (severe Staphylococcus (MRSA), streptococcal infections + pseudomembranous colitis (C. Difficile).Pharmacokinetics:Penetrate well into tissue (peritoneal cavity, pericardium, valves, endocardium, pleura, joints)Not absorbed in GITExcreted by the kidneys unchangedVancomycin: t1∕2 of 6-8 hs,

Syndrome "red neck" or "red man" (flushing of the upper body, spasm of the thoracic muscles, breathing difficulty);

Makulo-like or urticaria rash, allergic reactions;

Reversible nephrotoxicity;

Ototoxicity;

Transient neutropenia or thrombocytopenia

Side effects of Vancomycin

Fosfomycin

Well absorbed, well penetrates into various organsand tissues.

Mechanism of action: blocks cell wall synthesis m/oby inhibiting enolpyruvylshikimate (involved in thesynthesis of precursors peptidoglycan).

Spectrum: broad, but more often is used to treat Gr"-" -infections: E. coli, Salmonella, Klebsiella, Proteus,including bacteria resistant to other AB.

Indications: orally: acute and recurrent cystitis,urethritis, bacteriuria in pregnant women, preventionUGT-infection in transurethral studies andinterventions; i.v. or i.m. - in severe infections of variouslocalization

nausea, vomiting, diarrhea.

allergic reactions: rash, urticaria, itching

when parenteral application: transient increase in liver transaminases, anaphylactic shock, pancytopenia, headache, dizziness, phlebitis/infiltration at the injection site.

Side effects of fosfomycin

Bactericidal antibiotics

II. Inhibition of cytoplasmic membrane

➢ DaptomycinRA: i.v. 1 time a day, not metabolized, excreted by the kidneysMechanism: cyclic lipopeptide → there are hydrophilic core

and hydrophobic tail → irreversibly binds to the cellmembrane Gr " + " bacteria → channel is formed → outputK+ → rapid depolarization → inhibition of synthesis ofprotein, DNA and RNA → cell death

Spectrum: narrow, Cr " + " including Clostridium, strepto -and poly-resistant: staphylo - and enterococci (MRSA andvancomycinresistant, E. faecium).

Indications: complicated skin and soft tissue infections,bacteremia and infectious endocarditis caused by MRSA

Side effects: allergic reactions, transient increase in AST andALT, reversible myopathy (rarely)

Lipopeptides

Bacillus polymyxa produces 3 polypeptides: polymyxins M, B,E.Toxicity, are used locally.Not absorbed. Do not pass the BBB. Metabolized in the liver,excreted by kidneys.Spectrum: narrow, Gr" -": P. aeruginosa, Acinetobacter andenterobacteriaMechanism: polymyxins (are cationic compounds) areembedded in the CPM and "dissolve" it (cationic detergent)→ lysis of bacteria.Indications: p. aeruginosa and enterobacteriainfections(reserve);Side effect: NephrotoxicityNeurotoxicity and neuromuscular blockade

Polymyxins

➢Colistimethate - derived methansulfonate acid colistin(polymyxin E).

RA: Powder for solution for inhalationIndications: P. Aeruginosa respiratory infections,

mucoviscidosis.Side effect:Allergic reactions (angioedema);Paresthesia, dizziness;Bronchospasm, ↑ sputum, pharyngitis, dyspnea;Acute renal failure

Sodium colistimethate

Bacteriostatic antibiotics

Bind to the 50S:macrolideslincosamideschloramphenicoloxazolidinones

Bind to the 30S:aminoglycosidestetracyclinesglycylcyclines

Antibacterial agents that inhibit protein synthesis

I. Macrolides

Antimicrobials that Bind to the 50S Ribosomal Subunit

Mechanism of action

Interact with 50S ribosome and inhibit translocase →disrupt the promotion of ribosome mRNA

General property:

Predominantly bacteriostatic action.Spectrum: narrow, Gr " + " kokki (strepto-, staphylo-) and

intracellular pathogens (Mycoplasma, chlamydia, Legionella).

Low toxicity.The absence of cross-Allergy to β-lactams.

Classification

Natural

(acid-proof, t1/2 1,5 h)Semi-synthetic

(acid-fast, t1/2 is 35 h)

14-members Erythromycin Clarithromycin

15-members Azithromycin

16-members Spiramycin

Josamycin

Spectrum: narrow (mostly Gr "+") or broad, depends on the dose

and drug.

Gr " + " cocci: staphylo -, including penicillin resist. S. aureus, Streptococcus and pneumococcus;

Gr "+" bacillus: corynebacteria diphtheria, Listeria;

Gr "-" cocci: Moraxella of catarhalis;

G-bacillus: Bordetella, pertussis, Haemophilus influenzae, Bacillus, Campylobacter, Helicobacter;

Pathogens of intracellular infections: chlamydia, Mycoplasma, spirochetes, Legionella

- Streptococc infection in patients with penicillin Allergy (tonsillopharyngitis, scarlet fever, rheumatic fever prevention).- Community-acquired pneumonia, including atypical.- Diphtheria.- Pertussis.- Orodental infections (periodontitis, etc.).- Campylobacteriosis.- Infections of the skin and soft tissues.- Chlamydial and Mycoplasma infection.- Syphilis- Legionellosis.- H. pylori eradication in peptic ulcer disease (clarithromycin)

Indications

↑ intestinal motility due to stimulation of motiline

receptors - motiono-like syndrome (erythromycin,

spiramycin, josamycin);

Pyloric stenosis in newborns (erythromycin,

clarithromycin, azithromycin)

↑ levels of hepatic transaminases, cholestatic hepatitis,

jaundice (erythromycin, clarithromycin);

↑ QT interval on ECG, reversible ototoxicity (i.v. high

doses);

Allergic reaction.

Side effects

II. Lincosamides

Lincomycin

Clindamycin

Mechanism: binds to 50S bacterial ribosome and inhibits the peptide portion of peptidyltransferase →inhibition of protein synthesis in bacterial cell.

Bacteriostatic Narrow spectrum of activity: gram-positive cocci and

non-sporadic anaerobes + some protozoa (Toxoplasma gondii, Pneumocystis).

High concentrations in bones and joints. Poor penetration through the BBB. The absence of cross-Allergy to β-lactams. Relatively frequent development of antibiotic-

associated (C. difficult-associated) diarrhea.

General property of lincosamides

Indications:⚫ Streptococcal tonsillopharyngitis.⚫ Aspiration pneumonia, lung abscess, empyema.⚫ Infections of the skin and soft tissues, bones and joints.⚫ Intra-abdominal infections: peritonitis, abscess.⚫ Infection of the pelvic organs are: endometritis, adnexitis,

oophoritis, postoperative anaerobic vaginal infections.⚫ Chloroquinine-resistant tropical malaria (clindamycin).⚫ Toxoplasmosis (clindamycin).⚫ Bacterial vaginosis (local).

Acne (locally).

Indications

Antibiotic-associated diarrhea, pseudomembranous colitis (C. difficult-associated).

Increased activity of liver enzymes.

Neuromuscular blockade (in high doses).

Allergic reaction.

Side effects

III. Chloramphenicol

Mechanism: reversibly binds to 50S and inhibits

peptidyltransferase → prevent peptide bond formation

Spectrum: broad : Salmonella, anaerobes (bacteroids), meningococcus and Rickettsia.

Indications:Bacterial meningitis, brain abscessGeneralized forms of salmonellosis, typhoid feverRickettsiosis (ku-fever, typhoid fever, etc.) Brucellosis!Gas gangreneBacterial infections of eyes (locally)

Reversible anemia, leukopenia, thrombocytopenia (dose-dependent);

Aplastic anemia (idiosyncrasy of chloramphenicol 1:10 000 – 40 000, does not depend on dose and number of doses, mortality 50-100%)

Neurotoxicity (psychosis, perif. neuropathies);

Dermatitis;

"Grey collapse" of the newborn ("Grey baby syndrome"): vomiting, abdominal distension, respiratory distress, cardiotoxicity, cyanosis collapse, hypothermia, acidosis. The reason: insufficient conjugation in the liver + functional imperfection of the renal tubules (the first 2-4 weeks of life).

Side effects

IV. Oxazolidinones

Linezolid

Mechanism: interacts with the 50S and prevents formation of the initiation complex (mRNA, tRNA, and 50S).

Spectrum: narrow, C "+": cocci resistant to other antibiotics including MRSA, penicillinresistant pneumococci, enterococci vancomycinresistant; anaerobic bacteria: Clostridium (except C. difficile), nekot. strains of B. fragilis, Peptostreptococcus.

Indications: Nosocomial infection of any localization caused by

MRSA, community-acquired pneumonia, complicated infection: intraabdominal , skin and soft tissues.

Reversible anemia and thrombocytopenia;

Increased activity of transaminases and AF, increased levels of bilirubin in the blood;

Dyspepsia;

Headache

Side effects

Antimicrobials that Bind to the 30S Ribosomal Subunit

I. Tetracyclines

Tetracycline

Doxycycline

Mechanism: bind to 30S and inhibit binding of aminoacyl-tRNA to the aminoacyl center (inhibit initiation)

Spectrum: broad: Gr " + " bacillus: Listeria, anthrax wand, P. acne;Gr " + " bacillus: H. pylori (tetracycline), H. influenzae, cholera Vibrio, causative agents of plague, tularemia and brucellosis;Intracellular pathogens: chlamydia, Mycoplasma, Legionella, Rickettsia;Spirochete: Treponema pallidum

Indications: ⚫ genital chlamydia and Mycoplasma infections, ⚫ syphilis and gonorrhoea - in case of β-lactam

intolerance)⚫ Atypical pneumonia⚫ Peptic ulcer disease (H. pylori eradication, only

tetracycline)⚫ Acne⚫ plague, cholera, anthrax ⚫ Rickettsiosises⚫ Zoonoses (leptospirosis, brucellosis, tularemia)

HepatotoxicityPhotosensitization (rash, dermatitis, nail damage due to sunlight)Antianabolic action (↓ synthesis ↑ protein catabolic)In children: violation of bone development (deceleration of their longitudinal growth) and teeth (change in color of teeth, enamel defects)*

** form chelate compounds with calcium orthophosphate

Side effects

children up to 8 years

pregnancy and breast-feeding

severe pathology of the liver

renal failure (except doxycycline)

Contraindications

II. Aminoglycosides

I generation II generation III generation

Streptomycin Gentamycin Amikacin

Kanamycin Tobramycin

Classification

Mechanism: Interact with 30S, causes misreading of mRNA →

synthesis of functionally inactive proteins and cell death (bactericidal

effect!)

Spectrum: broad, the main clinical importance: aerobic Gr " - ": enterobacteria and Pseudomonas aeruginosa (gentamicin, amikacin), as well as infectious endocarditis ++ M. tuberculosis (streptomycin, kanamycin and amikacin)++ Gr + cocci: Staphylococcus aureus, Streptococcus (in combination with aminopenicillins or cephalosporins)++ causative agents of plague, tularemia, brucellosisPneumococci resistant! Not active against anaerobes and intracellular microorganisms!

Enterobacteriaceae infections of different localization - II-III generations.

Pseudomonas aeruginosa infection- II-III generations. Enterococcal infections-gentamicin or streptomycin in

combination with penicillin or ampicillin. Tuberculosis - streptomycin, kanamycin, amikacin -

always in combination with other anti-TB drugs. Zoonotic infections: plague, brucellosis

(streptomycin); tularemia (streptomycin, gentamicin).

Indications

⚫ Ototoxicity (vestibular disorders, Meniere's syndrome, hearing loss up to complete deafness)

⚫ Nephrotoxicity (proteinuria, creatinine and blood urea)

⚫ Neuromuscular blockade (paresthesia, muscle weakness, respiratory arrest with rapid i.v. of high doses)

Side effects

III. Glycylcyclines

Tigecycline

Bacteriostatic, but for some m/o acts bactericidal.

Mechanism: binds to the special spiral region of the a-section 30S and blocks the penetration of aminoacyl-tRNA to the a-site of the ribosome and the addition of amino acids to the peptide chain.

Spectrum: broad: all anaerobes, G + cocci (includingMRSA, enterococci vancomycinresistant,penicillinresistant Str. pneumoniae), Gr " - "(Haemophillus spp., Moraxella catarrhalis, Neisseriahonorrhoeae, Citrobacter, multi-resistant strains ofAcinetobacter, Enterobacter spp., E. coli and Klebsiellaproducing β-lactamases of the extended spectrum andcarbapenemases), "atypical" bacteria (Leginella,Mycoplasma, Chlamydophila pneumoniae).

Not active against P. aeruginosa!

Indications:complicated skin and soft tissue infections, intraabdominal infections;community-acquired pneumonia.

Side effect:Nausea and vomiting, abdominal painHyperbilirubinemia , high level of AST, ALT, APh, urea in the blood, pancreatitisHypoproteinemiaPossible photosensitization and tooth damageAllergic cross-reaction with tetracyclines

Do not use in pregnancy, lactation and children below the age of 18 years

The Action of Antimicrobial Drugs

Foundation

Fig 20.2