Antimicrobials: Protein Synthesis Inhibitors Flashcards by Denisse Tiangco

Inhibits formation of initiation complex

Aminoglycosides

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Inhibits amino acid incorporation

Tetracycline

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Inhibits formation of peptide bond

Chloramphenicol

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Inhibits translocation

Macrolides

Lincosamide (Clindamycin)

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Agents that bind to 30s ribosomal subunit

Aminoglycoside

Tetracycline

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Agents that bind to 50s ribosomal subunits

Macrolides
Chloramphenicol
Lincosamide

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Bactericidal

Aminoglycoside

Cell wall synthesis inhibitors

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Bacteriostatic

Tetracycline
Macrolide
Chloramphenicol
Lincosamide

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“mycin”

Derived from streptomyces

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“Micin”

Derived from micromonospora

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Inhibits protein synthesis at the 30s ribosomal subunit

Excreted unchanged by

Aminoglycoside

kidneys

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Aminoglycoside examples

Excreted unchanged by kidneys

Amikacin
Netilmicin
Neomycin
Tobramycin
Gentamicin
Streptomycin

TANGS

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For UTI Gram negatives

Combined with penicillin and cephalosporin and or anti anaerobe
E coli
Enterobacter
Klebsiella
Pseudomonas
Tularemia

Aminoglycosides

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DOC for tularemia

Streptomycin

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Synergistic with beta lactam antibiotics
Bactericidal

Highly polar structure prevents adequate absorption after oral administration

All must be given IV to achieve serum levels except neomycin

Aminoglycoside

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Only aminoglycoside given topically or orally

Neomycin

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Aminoglycosides cause

Ototixicity
Nephrotoxicity

as well as Cisplatin

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Aminoglycosides are bactericidal because

1 they bind to outer bacterial membrane thereby disrupting membrane integrity
2 bind to ribosomal 30s subunit

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Interferes formation of initiation complex
Induce misreading of mRNA template
Cause polysomes to break up into monosomes
Concentration-dependent killing

Binding to 30s ribosomal subunit

Aminoglycosides

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Explains why aminoglycosides can be given in single daily doses despite short half-life

Concentration dependent (post antibiotic effect)

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2 days fluid diet, mechanical

Oral Metronidazole and Erythromycin 1 g and Neomycin

Nichols-Codon Bowel Prep for Colorectal Surgery

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Aminoglycoside adverse effects:

Ototoxicity
Nephrotoxicity - Acute Tubular Necrosis
Neuromuscular blockade

“triple punch of a mean guy”

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Aminoglycosides cause ototoxicity and nephrotoxicity because

they accumulate in the endolymph of the inner ear causing damage to hair cells in cochlea

and renal cortex

this is increased when taking diuretics

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Aminoglycosides cause nephrotoxicity because

they accumulate in the renal cortex

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Aminoglycosides cause neuromuscular blockade because

they decrease acetylcholine and decrease sensitivity to postsynaptic site

Aminoglycoside-induced neuromuscular blockade is reversed by

Ca gluconate | Neostigmine

Broadest spectrum of activity

Tetracycline

``` Activity against gram positive Gram negative Spirochetes Mycoplasma Rickettsia Chlamydia ```

Tetracyclines

Contains four fused rings with a system of conjugated double bonds Inhibits protein synthesis at 30s ribosomal subunit

Tetracyclines

Tetracyclines Cannot be given with milk and antacids because

They form stable complexes with divalent and trivalent cations. Divalent cations inhibit its absorption in the gut.

Tetracylines cause Milk Alkali Syndrome:

Hypercalcemia Alkalosis Renal failure inc Ca inc pH Renal failure

DOC for vibrio cholerae

Tetracycline

DOC for Mycoplasma

Macrolide

DOC for Rickettsia

Tetracycline

``` Covers Vibrio cholerae Acne Chlamydia Ureaplasma Urealyticum Mycoplasma Borrelia burgdorferi (Lyme disease) Rickettsia ```

Tetracycline VACUUM your Bed Room

``` For psittacosis inclusion conjunctivitis trachoma endocervical rectal infection and non specific urethritis ``` all by Chlamydia

Tetracycline

DOC in syphillis if allergic to penicillin

Tetracycline

For Brucellosis Cholera Acne

Tetracycline

Most common adverse effect of tetracycline

Nausea and vomiting

Tetracycline advserse effects:

Deposition in bones and primary dentition causing DISCOLORATION AND HYPOPLASA “teethracylcine” Fanconi syndrome Hepatotoxicity Phototoxicity Vestibular problems

Tetracycline may also cause this syndome

Fanconi’s syndrome nephrocalcinosis | rare renal tubule disorder causing excess amounts of glucose, bicarbonate, phosphates, uric acid, potassium, amino acids

Tetracyclines cause these symptoms

Enamel dysplasia | Inhibition of bone growth affecting epiphyseal plate also Quinolones

Tetracycline causing phototoxicity

Demeclocycline

Tetracycline causing vestibular problems

Minocycline

Only aminoglycoside given for Neisseria

Spectinomycin

Tetracycline with longest half life | and with highest protein binding

Doxycycline cleared renally and fecally without liver metab

Tetracycline with best absorption and tissue penetration

Minocycline

Tetracycline contraindications:

Pregnant Children under 8 years Teratogen and teeth stainer

Covers gram negative: H influenzae, N meningitidis, N gonorrhea, Salmonella typhi, Brucella, Bordetella pertussis Anaerobic gram positive cocci: C tetani, Mycoplasma E coli, V. cholerae, Shigella, Chlamydia, Mycoplasma Not effective against Pseudomonas, Histolytica, Entamoeba

Chloramphenicol | Chloromycetin

``` Used for tyhpoid fever Bacterial meningitis Anaerobic infections Rickettsial disease (murine, scrub typhus, recrudescent typhus) Rocky Mountain Spotted Fever Q fever Brucellosis ```

Chloramphenicol

Current DOC for typhoid

Ceftriaxone

Chloramphenicol resistance

Acetylation of chloramphenicol by acetyl-transferase enzyme (acetylated form cannot bind ribosome) Decreased cellular permeability Mutation leading to ribosomal insensitivity

Because of potential toxicity, this should only be employed with a well-defined and indicated condition Acetylation by acetyl transferase - cannot bind ribosome, resistance Decreased cellular permeability

Chloromycetin | Chloramphenicol

Chloramphenicol AR

``` Anemia (dose dep) Aplastic anemia (dose INdep) Grey baby syndrome (lack of UDP- Glucoronyl transferase) ashen grey color of skin and lethargic eyes ```

Most important to toxicity of chloramphenicol is

Hematologic: Bone marrow aplasia (benzene) Idiosyncratic (aplastic anemia) Dose-related reactions: erythroid supression of bone marrow (hypocellular aslo Vinblastin, Vincristine)

Chloramphenicol should not be given with a

phenobarbital (shortens half life)

inhibits protein synthesis at 50s ribosomal subunit

Macrolide

From streptomyces erythreus Formerly Ilotycin Alternative to penicillin if with allergy Mainly for gram positives ineffective for gram neg Bacteriostatic at low conc Bactericidal at high conc

Erythromycin

Erythromycin activity

Static in low concentrations | Cidal in high concentrations

Covers Corynebacterium Chlamydia CAP (pneumococcus, mycoplasma, legionella) Staph Atypicals: Mycoplasma, Legionella Gram neg: Neisseria, Bordatella

Erythromycin

Allergy with penicillin drug of choice

Erythromycin

Allergy with erythromycin

Vancomycin IV

Allergy with Vancomycin

Aztreonam

Erythromycin base can be inactivated by

gastric acid

Esters of erythromycin base with improved acid stability and absorption less altered by food

stearate estolate ethylsuccinate

``` DOC for Legionnare’s disease Mycoplasma Campylobacter Chlamydial infection Diptheria Pertussis ``` Also covers for Gram positives: pneumococci, legionella, chlamydia, listeria, helicobacter, mycobacteria Gram negatives: neisseria, bordetella, bartonella, rickettsia, campylobacter, H influenzae (less susceptible)

Erythromycin | Macrolides

Adverse effects of erythromycin

Epigastric distress Cholestatic jaundice (estolate from erythromycin) GI: anorexia, nausea, vomiting, diarrhea Hepatitis, fever and rash

Erythromycin causes diarrhea because

it directly stimulates gut motility

IM injection of erythromycin may lead patient to experience

Pain for hours | Deafness (transient)

Erythromycin is an enzyme

Inhibitor of CYP450

Erythromcin increases levels of

``` Theophylline Oral anticoagulants Cyclosporine Digoxin Statin Corticosteroids Carbamazepine ```

Unique pharmacokinetic properties Extensive tissue distribution High drug concentration in cells (including phagocytes) resulting in greater tissue and secretion concentration compared to serum concentration Half life of 3 days! Does not inactivate CYP450

Azithromycin

once a day dosing | should not be given with food

Azithromycin

Used for nongonococcal urethritis caused by chlamydia, LRTI, PID, pharyngitis, Legionnaire

Azithromycin

More active against staph and streph Used in PUD antimicrobial protocol with omeprazole or lanzoprazole Given with or without food but extended release form as once a day dosing (with food to improve bioavailability)

Clarithromycin

Inhibits protein synthesis by binding to 50s ribosomal subunit of bacterial ribosome Exhibits cross resistance with macrolides

Clindamycin

Sulfur-containing antibiotics isolated from Streptomyces lincolnensis Resemble macrolides in antibacterial spectrum and biochemical mechanism of action but has cross resistance Inhibits 50s subunit

Lincomycin

Potent agent available for non-spore forming anaerobic bacteria (Bacteroides fragilis) But best for anaerobes like Bacteroides

Clindamycin

Aspiration pneumoniae | Anaerobics DOC

Clindamycin

Intraabdominal infection DOC

Metronidazole

Covers Gram positives: streptococci, staphylococci, pneumococci Anaerobes: Gram positive and Gram negative Bacteroides No activity against Enterococci, Gram negative aerobic bacteria

Clindamycin

Drug inducing C difficile infection

Clindamycin Ampicillin/Amoxicillin Cephalosporin Fluoroquinolone

Treats anaerobic infection Penetrating wounds of abdomen and gut Female genital tract infections Aspiration pneumonia*

Clindamycin

Clindamycin AE

Diarrhea Nausea Skin rash Pseudomembranous colitis*

Patterned after Nalidixic acid

Quinolones

Introduction of fluorine atom forming fluoroquinolones enhances antibacterial activity

Fluoroquinolone

Most potent fluoroquinolone

Ciprofloxacin

Fluoroquinolone inhibits DNA synthesis due to inhibition of

DNA Gyrase | Topoisomerase II and IV

First Gen Quinilone

Nalidixic acid | Non-fluorinated

Second Gen Quinolone

Ciprofloxacin -most potent fluorinated quinolone | Ofloxacin

Third generation quinolone

Gatifloxacin flourinated

Fluoroquinolone AE

``` Diarrhea* Nausea* Closure of epiphyseal plates* Headache Dizziness Nephrotoxicity Phototoxicity* ```

Fluoroquinolone absorption is decreased with

sucralfate antacid containing aluminum and magnesium iron and zinc

Antibiotic that can cause seizure

Fluoroquinolone

``` For UTI Skin Bone Soft tissue Respiratory tract infection Prostatitis STDs Diarrhea due to Campylobacter, salmonella, shigella, e coli ```

Fluoroquinolone

Fluoroquinolone examples

Ciprofloxacin Levofloxacin Norfloxacin Ofloxacin

Fluoroquinolone SE

``` Cartilage erosion in children (early closure of epiphyseal plate) * Tendonitis and tendon rupture in adults* Photosensitivity Headache and dizziness Insomnia Diarrhea, nausea ```

Used as urinary antiseptic Pregnancy Category B Contraindicated at term

Nitrofurantoin

Nitrofurantoin should not be given to nursing mothers because

it enters breast milk | discontinue

DOC for Chagas disease

Nifurtimox

Paul Ehrlich’s discovery of the antisyphilitic Salvarsan paved way for the creation of this drug

Sulfonamide

Metabolism of prontosil (bright red dye) in vivo to sulfanilamide (active drug)

Sulfonamide

Structural analog of PABA Competes with this substrate for enzyme Dihydropteroate synthetase preventing the synthesis of bacterial folic acid

Sulfonamide

Sulfonamide inhibits the enzyme

Pteridine synthetase or | Dihydropteroate synthetase

Trimethoprim inhibits formation of tetrahydrofolic acid by inhibiting the enzyme

Dihydrofolate reductase

Tetrahydrofolic acid is converted to

Thymidine Purine Methionine

Methotrexate inhibits the enzyme

dihydrofolate reductase

Sulfonamide inhibits the conversion of

P aminobenzoic acid to Pteridine

Trimethroprim inhibits the conversion of | Via enzyme

Dihydrofolic acid to tetrahydrofolic acid Dihydrofolate reductase

Essential cofactor for formation of Thymidine, Purines and Methionine

Folic acid

Well absorbed orally Displaces substances bound to albumin (bilirubin, warfarin) For gram positive and gram negative Nocardia, Chlamydia, E coli, Klebsiella; Enterobacter

Sulfonamide

UTI sulfonamide

Sulfamethoxsazole

Ulcerative Colitis | Crohn’s

Sulfasalazine

Burn infection

Silver sulfadiazine

Ocular infection

Sulfacetamide

Nocardiosis drug of choice

Sulfisoxazole

Toxoplasmosis

Sulfadiazine with pyrimethamine

Treatment of first attack of urinary tract infection

Co trimoxazole

In burn therapy to prevent and treat bacterial infection

Silver sulfadiazine | Mafenide

Treatment of conjunctivitis | Superficial ocular infections

Sodium sulfacetamide

Treatment of chloroquine resistant malaria

Quinine Pyrimethamine Sulfadoxime

Fansidar

DOC for pneumocystis carinii

Cotrimoxazole | Alternative drug: Pentamidine

Sulfonamide can

displace substances bound to albumin

Adverse Effects of Sulfonamide

``` Crystalluria Hematuria Rashes (SJS) Anemia (hemolytic) in patients with G6PD Nausea and vomiting Kernicterus ```

Sulfonamide is contraindicated in pregnancy because

it crosses placenta and breast milk

Drugs that most commonly cause SJS

Sulfonamide Aromatic Anticonvulsant Allopurinol

Mechanism of action is similar to sulfonamide

Sulfones

Used to treat leprosy

Dapsone Methemoglobinemia Hemolytic anemia G6PD

Associated with methemoglobinemia and hemolytic anemia G6PD Competes with PABA to prevent dihydrofolate reducatase

Dapsone

Dihydrofolate reductase inhibitor | Given with sulfamethoxazole

Trimethoprim

DOC for Pneumocystis carinii PCP Also used in complicated UTI, bacterial prostatitis, gonorrhea, sinusitis, AOM, pneumonia Also effective in chancroid, shigellosis, tyhphoid fever, Nocardiosis

Trimpethoprim

Trimethoprim SE

Leukopenia Megaloblastic anemia Granulocytopenia

Severe hypoxemia in immunocompromised

Pneumocystis carinii

prophylaxis for PCP is given if CD4 count is

<200

Prophylaxis for MAC is given is CD4 is

<50

Drugs CI in G6PD

Sulfonamides | Anti malarials

Drugs that induce SLE

Hydralazine Isoniazid Methyldopa Procainamide

Confer antibiotic resistance

Bacterial plasmids

Cidal = kills Cell wall synthesis inhibitors Narrow spectrum

Bactericidal

Static inhibits growth Protein synthesis inhibitors Broad spectrum

Bacteriostatic

Cell wall synthesis inhibitors

Penicillin Cephalosporin Carbapenem Monobactam

Aminoglycoside contraindicated in pregnancy:

Streptomycin

Aminoglycoside is CI in patients with

Myesthenia gravis

Tetracycline CI

Pregnant | Children under 8

Erythromycin

Inbibits CYP450 | Inc theophylline, digoxin

C difficile drugs

Clindamycin Ampicillin/Amoxicillin Cephalosporin Quinolone

Meningococcemia

First line: rifampicin | Second line: ciprofloxacin

Sulfonamide used to treat malaria

Fansidar (Sulfadoxine + Pyrimethamine)

Sulfonamide SE

``` Crystalluria hematuria SJS Anemia (hemolytic) in G6PD Nausea and vomiting Kernicterus Crosses placenta and breast milk - contraindicated ```

Loss of eyebrows, collapsed nasal bridge, aesthetic patches Erythema nodosum leprosum and multibacillary leprosy

Leprosy Give rifampin, dapsone, clofazimine