ANTIMICROBIAL PT 2

Perfect microcompre exam

BETA-LACTAMS

Inhibits cell wall synthesis by binding to penicillin binding proteins

penicillin binding proteins

responsible for the final stages of cross-linking of the bacterial cell wall structure.

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are enzymes that are located on the outer surface of bacterial cytoplasmic membrane.

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They are involved in cell wall synthesis during the replication process.

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They vary in size and number, and affinity to beta-lactam drugs. They are part of the normal membrane of both gm (+) and (-) bacteria.

R chain

gives the drug a unique characteristic.

Penicillin

**targets synthesis process of active living cells and preventing the cross linking of sugar of the peptidoglycan in the final stage.**

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active mainly against gm (+) organisms.

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acts directly on the cell wall by making it very weak.

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It also activates autolysin, a bacterial enzyme, to break down the wall for synthesis, growth, and cell division. Disrupting the cell wall synthesis and promoting the active destruction will subsequently result in the osmotic lysis of the bacterium. Thus, they are bactericidal.

carboxypeptidases, transpeptidases, and endopeptidases

types of PBN

o species that lack a cell wall e.g. Mycoplasma

o those with very impenetrable wall such as Mycobacteria

o intracellular pathogen such as Brucella, Legionella, Chlamydia

penicillin is not active against?

Pseudomonas aeruginosa

More recent beta-lactams are active against innately more resistant organisms like______

Methicillin-resistant staphylococci (MRSA)

synthesize an additional PBP which has much lower affinity for beta-lactams than the normal PBP and therefore is able to continue cell wall synthesis when the other PBPs are inhibited.

Vancomycin

last line of antibiotic for MRSA:

ALTERATION IN ACCESS TO THE TARGET SITE

Mutation in porin genes result in decrease permeability of the outer membrane and hence resistance.

Beta-lactamases

are enzymes that catalyze the hydrolysis of the beta lactam ring yields microbiologically inactive products.

LATERAL OR HORIZONTAL GENE TRANSFER (HGT)

a process whereby genetic material contained in small packets of DNA can be transferred between individual bacteria of the same species or even between different species.

Transformation

The organism disintegrated and went out to its external environment and it was absorbed by another microorganism.

Conjugation

direct cell-to-cell contact; a microorganism carrying the R plasmid and directly in contact with another microorganism and transferred the resistant gene; main mechanism of HGT

Transduction

a bacteriophage have needles that get R plasmid from one organism and transfer to another microorganism.

BETA-LACTAMASE INHIBITORS

has a very similar structure to beta-lactams which is why beta-lactamases bind here when they are combined with antimicrobials.

Hypersensitivity reactions

anaphylaxis

Cross-sensitivity

TOXIC EFFECTS OF BETA-LACTAM AGENTS

Pen G

is the most common drug implicated in drug allergy. It can cause acute and subacute reactions that can be mediated by IgG and IgE.

PENICILLINS

DOC for Syphilis

Pen G Na or K (IV, IM) → Benzylpenicillin

given parenterally because they are acid labile, in short, they will be destroyed by the acid in the stomach.

PO

Phenoxymethylpenicillin is administered thru

IM

Pen G procaine and Pen G Benzathine is administered thru

Penicillinase- resistant penicillin

higher affinity to the PBP and more resistant to destruction by enzymes produced by MO;

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can penetrate gm (-) bacterial wall through the porins;

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semi-synthetic penicillin.

Aminopenicillin

3rd generation penicillin; semi-synthetic;

broader spectrum of activity;

not deactivated by enzymes;

effective against gm (+) and many gm (-) bacteria like E. coli and H. influenzae;

susceptible to hydrolysis of beta-lactamases;

> not penicillinase resistant

Extended-spectrum penicillin

with additional antimicrobial activity aside from being active against gram (+) microorganisms.

Ureidopenicillins

susceptible to gastric acidity and beta-lactamases but has greater range of activity against gm (-) bacteria especially P. aeruginosa.

CARBAPENEM

broadest spectrum of activity among beta- lactams

last line of drug among the beta-lactams

greatest potency against bacteria which is why they are reserved for severe infections.

dihydropeptidase enzyme (DHP-1)

carbapenem is deactivated by what enzyme

cilastatin:

inhibitor of the enzyme added so it will not be metabolized immediately; no antimicrobial property.

Half-life

time it takes for the drug to be reduced in half in the body.

Aztreonam

the only available monobactam

monobactam

resembles aminoglycoside but does NOT cause ototoxicity and nephrotoxicity.

GLYCOPEPTIDES

are large molecules and act at an earlier stage than beta-lactams.

GLYCOPEPTIDES

They act on the cytoplasmic membrane where the synthesis of new cell wall subunit attached to lipid carrier happens..

Vancomycin -

must be given with care in renally impaired patient.

Teicoplanin

less toxic than vancomycin and can be given IV bolus and by IM inj.

Vancomycin

infection caused by gm (+) that are resistant to beta-lactam drugs

Previously DOC for pseudomembranous colitis

vancomycin was previously a DOC for_________

Metronidazole

DOC for pseudomembranous colitis

Red Man Syndrome

rapid infusion turns the patient to become reddish in color.

CYCLOSERINE

a broad spectrum antibiotic used as a second line agent for treatment of drug resistant tuberculosis.

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**can be bactericidal or bacteriostatic depending on its concentration and susceptibility of MO.**

CYCLOSERINE

MOA : Inhibits reactions involved in incorporation of alanine into cell wall precursor.

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competitively inhibiting two enzymes, L- alanine racemase and D- alanine: Dalanine ligase.

BACITRACIN

Poorly absorbed when given orally in the GIT

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Cyclic peptide or a mixture of polypeptide

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Active against a wide variety of gram (+) organisms

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given topically (if IM, causes nephrotoxicity)

Prevents dephosphorylation of phospholipid carrier, which prevents regeneration of carrier necessary for synthesis to continue.

MOA of bacitracin

MONOBACTAMS

active against gentamicin resistant organisms

Chloramphenicol, Macrolides, and Lincosamides

prevent peptide bond formation; stops protein synthesis.

Aminoglycosides

impair proofreading, resulting in production of faulty proteins.

Tetracyclines

block the binding of tRNAs, thereby inhibiting protein synthesis.

inhibit protein synthesis at the 30s ribosomal subunit causing mismatch between codons and anticodons leading to faulty proteins.

MOA of AMINOGLYCOSIDES

Amikacin

semisynthetic antibiotic that is derived from Kanamycin.

Intrathecal

given directly to the patient’s spinal fluid (meninges and cord)

Streptomycin

for treatment of TB meningitis

Gentamicin

gm (-) meningitis in neonates

ototoxicity, nephrotoxicity and neurotoxicity

adverse effect of AMINOGLYCOSIDES

TOBRAMYCIN

new aminoglycoside antibiotic with a broad spectrum of activity in vitro and pharmacokinetic property that is very similar to Gentamicin.

AMIKACIN AND NETILMICIN

Both are less active, but may be active against strains resistant to gentamicin and tobramycin.

STREPTOMYCIN

Now reserved almost entirely for the treatment of mycobacterial infections.

First line of drug for TB

NEOMYCIN

Not for systemic treatment, but can be used orally in gut decontamination regimens in neutropenic patients.

TobraDex®

Tobramycin + Dexamethasone

neutropenic

low WBC; inability to fight infections.

Gut Decontamination

refers to the practice of functionally removing the ingested toxin or microorganisms present in the GIT which a neutropenic patient cannot fight back because of their condition.

SPECTINOMYCIN

not an aminoglycoside but they have similar features.

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differs in that it does not contain amino sugar or glycosidic bond in its structure.

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Used to treat beta-lactam resistant N. gonorrhoeae.

o hospital acquired infection

o malignancy

o immunosuppressive therapy

o major trauma, surgery or major burns

o IV catheter

o urinary catheter

o extreme age

Septicemia of unknown etiology arising from:

Bacterial endocarditis

inflammation of endocardium

Penicillin

DOC for Gonorrhea:

discoloration and hypoplasia of the teeth (enamel is not formed)

o temporary stunting of growth (not given to children)

o phototoxicity (demeclocycline)

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o vestibular problems (minocycline).

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Adverse drug effects of tetracyline

CHLORAMPHENICOL

easily synthesized which is why it is the first antibacterial synthetically mass produced.

CHLORAMPHENICOL

DOC for typhoid fever

o Gray Baby syndrome – will accumulate on neonates and cause hypotension and cyanosis because of the decrease in the oxygen-carrying capacity of the blood.

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o Aplastic anemia and bone marrow depression – all types of cells are not produced correctly.

Adverse drug effects of chloramphenicol

Erythromycin, Clarithromycin, Azithromycin, Fidaxomicin

types of macrolides

Lincomycin & Clindamycin

types of lincosamides

Cholestatic jaundice– yellowing of the skin because of the obstruction in the bile and changes in the liver function.

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epigastric distress

Adverse effect of macrolides and lincosamides

TETRACYCLINE

Has activity against gram (+), gram (-), spirochetes, Mycoplasma, Rickettsia, Chlamydia

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Broadest spectrum antibiotic

ERYTHROMYCIN

Alternative to penicillin

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From Saccharopolyspora erythraea originally called Streptomyces erythreus

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first discovered in the soil of Iloilo by Dr. Abelardo Aguilar

sterate, estolate and ethyl succinate

have improved acid stability and their absorption is less altered by food.

CLARITHROMYCIN

More potent than erythromycin against streptococci and staphylococci

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for the treatment of H. pylori together with Omeprazole.

AZITHROMYCIN

broader spectrum of activity and fewer side effects than Erythromycin

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Should NOt be administered with food and on empty stomach.

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extensive tissue distribution and high drug concentrations within cells

FIDAXOMICIN

used to treat diarrhea caused by infection with Clostridium difficile.

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cannot be used for infections not associated with C. difficile.

LINCOMYCIN

Sulfur-containing antibiotics isolated from Streptomyces lincolnensis.

CLINDAMYCIN

used primarily to treat infections caused by susceptible anaerobic bacteria such as respiratory infections, septicemia and peritonitis.

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for patients with hypersensitivity to penicillin

Dihydropteroate synthetase

is an enzyme that catalyzes an essential reaction in the synthetic pathway of tetrahydrofolic acid (THFA).

tetrahydrofolic acid (THFA).

used for synthesis of purines and pyrimidines and therefore, for nucleic acid synthesis.

Trimethoprim

is a structural analog and an enzyme inhibitor of dihydrofolate reductase.

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These drugs inhibit the production of tetrahydrofolic acid and also thymidine, purine, and methionine which are all necessary for the replication of the DNA.

Cotrimoxazole

(Sulfamethoxazole + Trimethoprim)

mutant bacteria resistant to one agent are unlikely to be resistant to the other.

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the two agents act synergistically against some bacteria

Advantages of Cotrimoxazole

Stevens-Johnson Syndrome

a form of toxic epidermal necrolysis

Stevens-Johnson Syndrome

o Urine Precipitation / Crystalluria

o Leukopenia

o Folic Acid deficiency / decrease

o Aplastic anemia

Kernicterus

toxic effects of Cotrimoxazole

Solubility is low.

Usefulness for UTI

Large spectrum of activity

Folic acid synthesis blocker

Antimetabolite or analog of PABA

Pharmacokinetic Profile of sulfa drug

Kernicterus

brain dysfunction or toxicity caused by build-up of bilirubin.

QUINOLONES

Inhibits the DNA gyrase, preventing supercoiling of the bacterial chromosomes.

Fluoroquinolones

new chemical derivatives with improved activity

floroquinolones

not licensed to children due to Gastrointestinal disturbances (most common side effects) • Neurotoxicity (cause BBB)

Rifampicin

is the clinically most important rifamycin. It is one of the first line of drugs for TB.

RIFAMYCINS

Binds to RNA polymerase and blocks the synthesis of mRNA, therefore, blocking the transcription process.

Rifampicin

urine, sweat and saliva of treated patients turn orange.

Hepatic Cytochrome p450 Enzyme System

enzyme that could decrease the metabolism of a lot of drugs.

Rifampicin

prophylaxis of close contacts of meningococcal and Haemophilus meningitis

→ Disulfiram-like effect

medication for chronic alcoholism; may cause acute hypersensitivity (intoxication) when taken with alcohol even at small volume.

POLYMYXINS

disrupts the fatty membrane that will lead to the leakage of cellular molecules and inhibit the cellular respiration leading to cell death.

COLISTIN

also known as Polymyxin B and Polymyxin E.