Inhibitors Inhibitors of of Protein Protein Synthesis Synthesis

(1)

Inhibitors Inhibitors

of of

Protein Protein Synthesis Synthesis

AOB

(2)

Doxycycline

Oxytetracycline (top) Tetracycline HCl

Tigecycline (glycylcycline) Eravacycline (new)

Sarecycline (new)

Omadacycline (new) Tet rac ycl in

Tet rac ycl in es es

22

(3)

Eravacycline

• Sarecycline ^{is a}

tetracycline-derived antibiotic

• Approved by the FDA in October 2018 for the treatment of

moderate to severe acne vulgaris

• Omadacycline is a broad spectrum aminomethylcycline subclass of tetracycline antibiotics

• Approved in October 2018 for the treatment of community-

acquired bacterial pneumonia

and acute skin and skin

(4)

•

Inhibit protein synthesis in bacterial ribosomes

•

Enter bacteria through passive diffusion + energy- dependent active transport

•

Resistance through efflux pump [Tet(AE), Tet(K)], ribosome protection (Tet(M), enzymatic inactivation

•

many Gram + and

Gram – ^bacteria

including some anaerobes,

rickettsiae , chlamydia,

mycoplasma

₄₄

(5)

•

Oral absorption 60-100%, impaired by food (except for doxycycline)

•

Tigecycline, iv only

•

Oral drug alters intestinal flora..

GI adverse effects

•

Multivalent cations ; dairy, antacids and alkaline pH impaires absorption

•

Bind to and DAMAGE BONES (should not be used under age 8)

•

Distribution wide through tissues

•

ALSO PLACENTA, NOT TO CSF (except for

Pharmacokinetics

(6)

66

Tetracyclines Tetracyclines

(7)

Clinical Uses

• Infections by «atypical» pathogens: Mycoplasma spp,

Ricketssiae spp, Chlamydia spp, Vibrio cholerae,

Brucella spp

(8)

Acute illness

fever, night sweats (with a strong, peculiar, moldy odor), arthralgia, myalgia, low back pain, and weight loss as well as weakness, fatigue, malaise, headache, dizziness,

depression, and anorexia Chronic brucellosis

localized infection (generally

spondylitis, osteomyelitis, tissue abscesses, or uveitis) and/or

relapse in patients with objective evidence of infection

88

(9)

PROTOCOL-1

A LONG COMBINATION TREATMENT with AB Doxycycline - Streptomycin

Doxycycline + Rifampin

PROTOCOL-2

Quinolone

Alternatve treatment

(10)

Symptoms in women

•

An abnormal vaginal discharge

•

A burning sensation when urinating Symptoms in men

•

A discharge from their penis

•

A burning sensation when urinating

•

Pain and swelling in one or both

testicles (although this is less common) Men and women can also get infected with chlamydia in their rectum

Asymptomatic infection is common among both men and women

1010

(11)

Recommended Regimens

•

Azithromycin 1 g orally in a single dose

OR

•

Doxycycline 100 mg

orally twice a day for 7

days

(12)

•

Spread by drinking water or eating food contaminated with Vibrio cholerae

•

Severe cholera is characterized by large amounts of watery diarrhea, often

described as “rice-water stool” due to pale, milky appearance

•

It can also be accompanied by nausea and vomiting

•

If untreated, the loss of fluid can be lethal

Cholera

1212

(13)

•

HYDRATION

•

Tetracycline

•

Treatment with a single 300mg dose of doxycycline

•

Erythromycin for children and pregnant women

•

Zinc

(14)

1414

(15)

(16)

1616

• Tigecycline has a broader spectrum of activity

(Gram-positive pathogens: Enterococcus spp, vancomycin-resistant enterococci ( VRE ), Listeria, Streptococcus spp, MRSA ^and

Staphylococcus epidermidis

Gram-negative activity includes: Acinetobacter baumannii,

Citrobacter spp, Enterobacter spp, E. coli, Klebsiella spp,

(17)

…

yalnızca diğer alternatiflerinin uygun olmadığının

bilindiği ya da şüphelenildiği durumlarda kullanılmalıdır

^.

yetişkinlerde aşağıda belirtilen enfeksiyonların tedavisinde endikedir:

-

Metisiline dirençli Staphylococcus aureus (MRSA) da dahil komplike deri ve deri yapısı enfeksiyonları

-

Komplike intraabdominal enfeksiyonlar -

Bakteriyeminin eşlik ettiği vakalar dahil Streptococcus pneumoniae (penisiline duyarlı izolatlar), Haemophilus influenza (beta laktamaz negatif izolatlar) ve Legionella

pneumophila’nın neden olduğu toplum kökenli bakteriyel pnömoni.

https://www.tebrp.com/tebrp_plus/uygulama?operation=urun_d etay&u=MTk0Njc=

ADVERSE EFFECTS similar to tetracyclines

(18)

MACROLIDES and KETOLIDES

Erythromycin Azithromycin Dirithromycin Chlarithromycin Telitromycin

•

Resistance through reduced permeability of membrane or efflux pump, ribosome

protection, esterase-mediated hydrolization

•

Methylase production confers resistance to clindamycin and streptogramin B (MLS-type B resistance)

1818

(19)

•

clarithromycin (t

_1/2

6 hrs),

azithromycin (t

_1/2

40-68 hrs) and telithromycin have improved oral absorption, longer half-lives, and better tissue and intracellular penetration than erythromycin

Pharmacokinetics

(20)

Q. Time-dependent vs concentration-dependent killing?

Q. Examples?

²⁰²⁰

(21)

+ telitromycin + telitromycin Statins

Statins

(22)

Clinical Uses-Erythromycin

• Corynebacterial infections

(diphteria, corynebacterial sepsis)

• Chlamydial infections

2222

(23)

Upper respiratory tract infections ^;

azithromycin, clarithromycin, and telithromycin have activity against erythromycin-susceptible Streptococcus pneumoniae, Haemophilus spp, Moraxella catarrhalis, and atypical

pneumonia pathogens , including Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae

Telithromycin

Telithromycin also has activity against many erythromycin-resistant S. Pneumoniae

The gram-negative spectrum

E. coli, Salmonella spp, Yersinia enterocolitica, Shigella spp,

Campylobacter jejuni, Vibrio cholerae, Neisseria gonorrhoeae, and

Clinical Uses

(24)

erythromycin, clarithromycin, and azithromycin are preferred for the treatment of pertussis in persons ≥1 month

Bordetella pertussis

Diphtheria, tetanus, and pertussis (DTaP)

vaccines for children <7

Whooping Cough (Pertussis) Vaccination

2424

(25)

Clinical Uses-Azitromycin

• Penetrates BETTER into most tissues except for CSF, slowly released to provide a VERY LONG t

_1/2

• Chlamydial cervicitis, urethritis, community-acquired pneumonia

• Empty stomach, DOES NOT inhibit CYPs

Toxoplasma

(26)

Adverse Adverse

•

Gastrointestinal side effects (nausea, diarrhea, abdominal pain)

•

Stimulation of GI peristaltism

•

Hepatotoxicity

•

QT interval prolongaton and cardiovascular events

(FDA warning for clarithromycin and azitromycin for CV events)

•

Hearing loss

•

Anaphylaxis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS),

pseudomembranous colitis, and exacerbations of myasthenia gravis

Q. What is QT prolongation? What are the consequences?

2626

(27)

CLINDAMYCIN-another protein synthesis inhibitor

•

A lincosamide antibiotic approved by FDA for the treatment of anaerobic, streptococcal, and

staphylococcal infections

•

Its major disadvantage: antibiotic-associated diarrhea, including Clostridioides (formerly Clostridium) difficile colitis

•

Achieves high intracellular levels in phagocytic cells, high levels in bone

•

Considered a bacteriostatic, but is bactericidal against some strains of staphylococci, streptococci, and

anaerobes such as Bacteroides fragilis

(28)

Chloramphenicol (Gemycetin®)

•

Broad-spectrum, active against aerobic/anaerobic, Gram + and –

•

Oral and parenteral forms are prodrug

•

RARELY used systemically in US; systemic drugs no longer produced in Turkey

•

Topical use for eye infections

Q. What is grey baby syndrome?

²⁸²⁸

(29)

ALERT: US Boxed Warning ALERT: US Boxed Warning

Blood dyscrasias:

Serious and fatal blood dyscrasias ( aplastic anemia, hypoplastic anemia, thrombocytopenia, and granulocytopenia ) are known to occur after the

administration of chloramphenicol. In addition, there have been reports of aplastic anemia attributed to

chloramphenicol which later terminated in leukemia. Blood dyscrasias have occurred after both short-term and prolonged therapy with this drug.

Chloramphenicol must not be used when less potentially

dangerous agents will be effective. It must not be used in the

treatment of trivial infections or where it is not indicated, as in

colds, influenza, infections of the throat; or as a prophylactic

(30)

A synthetic antimicrobial drug Oxazolidinones: LİNEZOLİD

3030

(31)

(32)

• Use of linezolid is generally reserved for treatment of

infections due to drug-resistant organisms (eg, MRSA, VRE)

• Not a preferred agent in treatment of infections requiring prolonged therapy (ie, >2 weeks) due to the risk of serious

hematologic and neurologic toxicity

INDICATIONS

3232

(33)

AMINOGLYCOSIDES

(34)

AMINOGLYCOSIDES

Streptomycin Amikacin

Gentamicin

Neomycin (top) Tobramycin

Netilmicin

3434

(35)

•

Penetrate the organism by disrupting the magnesium and calcium bridges between lipopolysaccharide moieties

•

They are transported across the cytoplasmic membrane in an

energy-dependent (and oxygen-dependent) manner

(36)

3636

Pharmacokinetics

• HIGHLY POLAR

• No entry to CNS, except for active inflammation

• POSTANTIBIOTIC EFFECT

• CONCENTRATION-DEPENDENT KILLING

• Cleared by kidneys; traditional dosing if renal impairement

• No need to check serum levels for once

daily dosing (aim:<1mcg/mL between 18-

24 hrs after dosing)

(37)

•

Resistance among Gram - through acquisition/upregulation of genes that encode inactivating enzymes or efflux

systems

•

Emergence of resistance in Gram - bacilli during treatment

with aminoglycosides occurs infrequently

(38)

•

Despite the relatively broad spectrum of activity of

aminoglycosides, widespread clinical use is limited because of the availability of alternative, less toxic agents with

comparable efficacy and without the need for serum drug concentration monitoring

•

The most common clinical application (alone or as part of combination therapy) of AGs is for the treatment of serious infections caused by aerobic Gram - bacilli (including

Enterobacteriaceae, Pseudomonas spp, Acinetobacter spp, and Haemophilus influenzae)

•

While less common, AGs (in combination with other agents) have also been used for the treatment of select Gram + infections

Clinical Use

3838

(39)

Tularemia — Streptomycin and gentamicin are first- line agents, although other options may be used in

less severe cases

Francisella tularensis

Mo no the rap y

Plague — Streptomycin and gentamicin are first-line agents,

although other options may be used in patients who cannot tolerate aminoglycosides

BLACK DEATH: killed 25 million people across Europe during the first deadly pandemic in the mid-14^th Century

(40)

4040

Urinary tract infections due to multidrug- resistant (MDR) gram-negative organisms

Mo no the rap y

(41)

•

Creams, oinments, solutions of gentamycin for infected burns, wounds, skin lesions

•

Or to prevent catheter infections

•

Effectiveness unclear

•

Neomycin for topical use

(42)

Adverse

• In high doses, curare-

like effect that results in respiratory paralysis

• Usually reversible by

calcium gluconate or

neostigmine

(43)

(44)

RNA protein DNA

(45)

Antimicrobial Activity Antimicrobial Activity

Gram + and Gram – E.Coli

Klebsiella pneumonia Salmonella

Shigella

Enterobacter sp

Rickettsiae ARE STIMULATED

(46)

Resistance Resistance

Overproduction of _?__

Production of sulfonamide

(less) sensitive dihyropteroate synthase

Impair permeability to sulfonamides

(47)

Short acting

Intermediate acting

Long acting

Combination

sulfisoxazole

Sulfamethoxazole (in combination only) Sulfadiazine

(no longer available, risk of Stevens Johnson!)

Sulfadimetoxine

Sulfamethoxipyrazine

Pharmacokinetics

(48)

Pharmacokinetics Pharmacokinetics

Oral/ perenteral

Wide tissue distribution

Partial metabolism in liver

Excretion through GF

(49)

Clinical Use Clinical Use

• Pyrimethamine, the most effective drug against toxoplasmosis

• Pyrimethamine is a folic acid antagonist; dose-related suppression of the bone marrow

• Concurrent administration of folinic acid (leucovorin)

• A second drug, such as sulfadiazine or clindamycin (if the patient has a hypersensitivity reaction to sulfa drugs), should also be included

Inhibitors Inhibitors of of Protein Protein Synthesis Synthesis