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Antimicrobial Drugs. Classification of Antibiotics by Mechanism of Action. Inhibition of cell wall synthesis Beta-lactam drugs Penicillins Cephalosporins Carbapenems The others Cycloserine Vancomycin bacitracin. Classification of Antibiotics by Mechanism of Action.

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Antimicrobial Drugs

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Antimicrobial drugs l.jpg

Antimicrobial Drugs


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Classification of Antibioticsby Mechanism of Action

Inhibition of cell wall synthesis

Beta-lactam drugs

Penicillins

Cephalosporins

Carbapenems

The others

Cycloserine

Vancomycin

bacitracin


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Classification of Antibioticsby Mechanism of Action

Disruption of cell membranes

Polymyxin

Polyenes (anti-fungal agents)


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Classification of Antibioticsby Mechanism of Action

Inhibition of protein synthesis

Reversible inhibition (bacteristatic)

Chloramphenicol

The tetracyclines

The macrolides (erythromycin)

Clindamycin

Streptogramins

Linezolid

Irreversible – the bactericidal aminoglycosides


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4. inhibition of nucleic acid synthesis

1. rifamycins (RNA)

2. quinolones (DNA)

5. antimetabolites (folate metabolism)

1. trimethoprim

2. sulfonamides


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Susceptibility and Resistance

In vitro values are guides, not rules

In vivo, bug is resistant if cidal concentrations are toxic to the host

Achievable serum concentrations are what determine susceptibility or resistance to drug

Low pH, high protein concentrations, anoxia

Pharmacological parameters of drugs (serum versus other bodily fluids)

Kirby Bauer Plate


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Bacterial Mechanisms of Resistance

Prevent antibiotic from reaching its target

Destroy or inactivate antibiotic before it reaches target

Alter target


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Choosing the right antibiotic – is it really needed?

Nature of the illness – is it a bacterial infection or something else?

Presumptive diagnosis (based on history and clinical symptoms)

Empiric therapy – broad spectrum drug

Specific therapy – narrow spectrum


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Choosing the right antibiotic – pharmacokinetic considerations.

Location of infection

Some antibiotics may or may not reach therapeutic concentrations in certain bodily fluids (ex. CSF and urine)

Degree to which antibiotic binds serum proteins

Excessive binding will affect passive diffusion of antibiotic from serum to tissue


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Choosing the right antibiotic – host factors.

Status of host immune system (cidal vs. static)

Local environment of infected site (pus, foreign bodies, etc)

Age (organ function in newborns and elderly)

Inherited metabolic disorder

Pregnancy (fetal or neonatal development)


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Choosing the right antibiotic – host factors.

drug allergies

Rashes

Anaphylaxis

Co-morbid conditions are aggravated by some antibiotics

Seizures

Blood disorders

SJS Syndrome


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When you you use it, You loose it


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The Consequences


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General Outline for Antibiotics

Chemistry

Effect on microbes

Spectrum of coverage

Mechanism(s) of action

Mechanism(s) of resistance

Pharmacology of antibiotic class

Absorbance

Fate after absorption

Excretion

Pharmacology of select agents

Therapeutic uses

Toxicity/contraindications

Common (> 10%)

Uncommon (1-9%)

Rare (< 1%)


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Sulfonamides

Analogues of para-aminobenzoic acid

Broad spectrum

Competitive inhibitors of dihydropteroate synthase – needed for folic acid synthesis


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Sulfonamides


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Sulfonamides

  • Cidal in urine

  • Mechanisms of resistance

    • Altered affinity of enzyme for drug

    • Decreased permeability or active efflux

    • New pathway of folic acid synthesis


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Sulfonamides

Mostly absorbed from GI tract

Binds variably to serum albumin

Wide tissue distribution, including transplacentally

Variably inactivated in liver by acetylation and then excreted in urine

Some agents can precipitate in acid urine


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Rapidly Absorbed and EliminatedSulfonamides

Bind extensively to plasma proteins

Highly concentrated in urine (cidal)

Sulfisoxazole, sulfamethoxazole, sulfadiazine

Sulfamethoxazole combined with trimethoprim (Bactrim) is widely used to treat a variety of infections (esp. UTI)


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Poorly Absorbedin GI tract Sulfonamides

Sulfasalazine

Used to treat ulcerative colitis and irritable bowel syndrome

Gut flora metabolize drug into 2 compounds, 1 toxic, 1 therapeutic (5-aminosalicylate)

Ulcerative Colitis


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Sulfonamides forTopical Use

Sulfacetamide

Good penetration in eye

Non-irritating

Silver sulfadiazine

Prevention and treatment of burn wound infections

Bacterial corneal infection


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Long Acting Sulfonamide

Sulfadoxine

Serum half-life is measured in days rather than minutes or hours

Combined with Pyrimethamine to treat malaria

Plasmodium vivax


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Therapeutic Uses of Sulfonamides

Urinary tract infections

Nocardiosis:

Nocardia asteroides

Nocardia brasiliensis

Toxoplasmosis (avoid using in pregnant women)

Nocardiaasteroides


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Toxicity/Contraindications of Sulfonamides - UT

Crystallization in acid urine

Common to uncommon depending on drug

Alkalize urine or increase hydration


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Toxicity/Contraindications of Sulfonamides - blood

Acute hemolytic anemia

Rare to extremely rare

Associated with glucose-6-phosphate dehydrogenase activity in RBC

Agranulocytosis (extremely rare)

Aplastic anemia (extremely rare)


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Toxicity/Contraindications of Sulfonamides - immune

Hypersensitivity reactions (common to uncommon)

Skin and mucous membrane manifestations (rashes)

Serum sickness

Focal or diffuse necrosis of the liver (rare)


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Toxic Epidermal Necrolysis (TEN)


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Toxicity/Contraindications of Sulfonamides - miscellaneous

Nausea, anorexia, vomiting (common)

Kernicterus

Displacement of bilirubin from plasma albumin to brain resulting in encephalopathy

Never give sulfa drugs to a pregnant or lactating woman

Potentiation of oral anticoagulants, sulfonylurea hypoglycemic drugs, and hydantoin anticonvulsants

Bilirubin deposits in neonatal brain


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The Quinolones

Naladixic acid was a byproduct of chloroquine synthesis

Current drugs are fluorinated 4-quinolones

Broad coverage (some broader than others)

Targets DNA topoisomerase II (DNA gyrase) (G-) and topoisomerase IV (G+)

Resistance due to efflux and mutations in targets


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Quinolones

Favorable pharmacological attributes

Orally administered, quickly absorbed, even with a full stomach

Excellent bioavailability in a wide range of tissues and body fluids (including inside cells)

Mostly cleared by the kidneys

Exceptions are pefloxacin and moxifloxacin which are metabolized by liver

Ciprofloxacin, ofloxacin, and pefloxacin are excreted in breast milk


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Therapeutic Uses of Quinolones

Urinary tract infections

Prostatitis

STD’s

Chlamydia

Chancroid

Not syphilis or gonorrhea (due to increased resistance)


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Therapeutic Uses of Quinolones

GI and abdominal

Travelers diarrhea

Shigellosis

Typhoid fever


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Therapeutic Uses of Quinolones

  • Respiratory tract

    • All work well against atypical pneumonia agents (eg, chlamydia, mycoplasma, and legionella),

    • New agents for strep. Pneumonia

    • Respiratory fluoroquinolones: Levofloxacin, gatifloxacin, gemifloxacin, and moxifloxacin.

    • are effective and used increasingly for treatment of upper and lower respiratory tract infections.


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Therapeutic Uses of Quinolones

Bone, joint, soft tissue

Ideal for chronic osteomylitis

Resistance developing in S. aureus, P. aeruginosa, and S. marcesens

Good against polymicrobial infections like diabetic foot ulcers


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Therapeutic Uses of Quinolones

Ciprofloxacin for anthrax and tularemia (Francisella tularensis)

Combined with other drugs, useful for atypical Mycobacterium sp. or for prophylaxis in neutropenic patients

Pulmonary Anthrax


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Toxicity/Contraindications of Quinolone

Nausea, vomiting, abdominal discomfort (common)

Diarrhea and antibiotic-associated colitis (uncommon to rare)

CNS side effects

Mild headache and dizziness (common to rare)

Hallucinations, delirium, and seizures (rare)

May damage growing cartilage and cause an arthropathy. Thus, these drugs are not routinely recommended for patients under 18 years of age (common)

Quinolones not given to children unless benefits outweigh the risks

Leukopenia, eosinophila, heart arrhythmias (rare)


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The Beta-Lactams


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Penicillins

Penicillium notatum produces the only naturally occuring agent – penicillin G or benzylpenicillin

P. chrysogenum produces 6-aminopenicillanic acid, raw material for

semi-synthetics


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Penicillins

Spectrum of activity based on R groups added to 6-aminopenicillanic acid core

All are bactericidal and inhibit transpeptidases

Mechanisms of resistance

Alter affinity of transpeptidase

Enzymatically cleave the beta-lactam ring

Efflux pumps

Poor penetration into cell


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Penicillins

Administered orally, intramuscularly, or intravenously depending on agent

After oral dose, widely distributed in tissues and secretions (except CNS, prostatic fluid, and the eye)

Do not kill intracellular pathogens

Food interferes with adsorption

Rapid elimination through kidney, secreted in breast milk


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Penicillins G and V

Effective against aerobic G+ organisms except Staphylococcus, Pen G active against Neisseria and anaerobes

2/3 of oral Pen G destroyed by stomach acid, Pen V is more resistant so more is delivered to serum

Rapid elimination through kidney so probenecid is added to slow excretion.

Procaine, or benzathine forms of Pen G (im)


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  • Most drug is bound to serum albumin but significant amounts show up in liver, bile, kidney, semen, joint fluid, lymph, etc.

  • Cautious use in neonates and infants because renal function is not fully established

  • Patients with renal failure clear the drugs through liver although at a slow pace


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Penicillins G and V Therapeutic Uses

Streptococcus pneumoniae infections

S. pyogenes infections

Viridans strep endocarditis (also given prophylactically)

Anaerobes except Bacteroides fragilis group

Meningococcal infections

Syphilis and other diseases caused by spirochetes


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2. Isoxazolyl Penicillins

Oxacillin, cloxacillin, dicloxacillin, nafcillin

Designed to resist staphylococcal beta-lactamases

Like Pen V, stable in stomach acid but usually given parentally for serious staph infections

MRSA not covered

Absorption and fate of drugs after absorption, excretion similar to Pen G and Pen V


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3. Aminopenicillins

Ampicillin and amoxicillin

Broad spectrum

Not effective against beta-lactamase producers

Beta-lactamase inhibitors extend spectrum (clavulanic acid, sulbactam, tazobactam)

Both are acid resistant but amoxicillin is better absorbed, even with food

Don’t bind plasma proteins as much as predecessors

Secreted through the kidney


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AminopenicillinsTherapeutic Uses

Upper respiratory tract infections

Otitis media

Uncomplicated UTI

Acute bacterial meningitis in kids

Typhoid fever


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4. A Carboxypenicillin and a Ureidopenicillin

Ticarcillin and piperacillin

Ticarcillin is anti-Pseudomonas drug

Piperacillin + tazobactam has the broadest spectrum

Given parentally

Used for serious infections


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Toxicity/Contraindications of Penicillins

Hypersensitivity reactions (uncommon)

Rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, SJS, anaphylaxis

Drugs act as haptens when bound to serum proteins

Rashes will disappear when drug is withdrawn or can treat with antihistamines

For patients with allergies, switch to a different class of antibiotics


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Toxicity/Contraindications of Penicillins

GI disturbances with oral penicillins.

Large doses given to patients with renal failure can cause lethargy, confusion twitching and seizures

Sudden release of procaine can cause dizziness, tinnitus, headache and hallucinations

Pseudomembranous colitis

(Ampicillin).


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Cephalosporins

Base molecule is 7-aminocephalosporanic acid produced by a Sardinian sewer mold

R groups determine spectrum of activity and pharmacological properties

Mechanism of action/resistance and class pharmacology essentially the same as penicillins


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First GenerationCephalosporins

Cefazolin, cephalexin, cephadroxil

Excellent against susceptible staph and strep

Modest activity against G-

Cefazolin given parentally, others orally

More than half of the drug is bound to plasma proteins

Excreted by kidneys unmetabolized

Good for staph and strep skin and soft tissue infections


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Second GenerationCephalosporins

Cefaclor, cefuroxime, cefprozil, cefotetan, cefoxitine, cefamandole

Modest activity against G+, increased activity against G-, works against anaerobes

Cefaclor and cefprozil given orally

Absorption and excretion same as first gen.

Good for treating

respiratory tract infections

intra-abdominal infections

pelvic inflammatory disease

diabetic foot ulcers


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Third GenerationCephalosporins

Cefotaxime, ceftriaxone, cefoperazone, cefpodoxime, cefixime

Broad spectrum killers

Drugs of choice for serious infections

No effect against Listeria and beta-lactamase producing pneumococci

Cefpodoxime and cefixime are given orally, others parentally

Most excreted by kidney

Therapeutic uses

Bacterial meningitis

(2 exceptions cefoperazone, cefixime)

Lyme disease

Life-threatening G- sepsis


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Fourth GenerationCephalosporin

Cefepime

Same antimicrobial spectrum as third generation but resists more beta-lactamases

Given parentally, excellent penetration into CSF

Good for nosocomial infections


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Toxicity/Contraindications of Cephalosporins

Hypersensitivity reactions (uncommon) essentially same as for penicillins

Cross-reaction between 2 classes


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  • Other adverse effects:

    • Pain at injection site

    • Phlebitis after iv

    • When given with aminoglycosides, may increase nephrotoxicity

    • Drugs containing methylthiotetrazole (eg cefamandole, cefaperazone, cefotetan) may cause hypoprothrombinemia and disulfiram-like reaction.


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Carbapenems

Imipenem, Meropenem, Ertapenem

Beta-lactam ring is fused to a 5 member ring system


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Carbapenems

Effect on microbes and pharmacology of carbapenems similar to penicillins

Wider G+ activity, G- and anaerobes

For pseudomonal infections: given with aminoglycosides

Parenteral administration

Drugs of choice for infections caused by Enterobacter.


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  • Imipenem

    -Rapidly inactivated by renal dehydropeptidase I.

    • Should be given in combination with an inhibitor (Cilastatin)

  • Adverse effects of imipenem-cilastatin: GI distress, CNS toxicity, partial cross-allerginicity with penicillins.


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  • Meropenem:

    • not metabolized by dehydropeptidases

    • less likely to cause seizures.

  • Ertapenem:

    • has longer half-life

    • Less effective against pseudomonas

    • Causes pain at site of injection


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Aztreonam – a monobactam

Works only on G-, including Pseudomonas aeruginosa

Useful for treating G- infections that require a beta-lactam because it does not elicit hypersensitivity reactions


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Toxicity/Contraindications of Carbapenems

Nausea and vomiting (common)

Hypersensitivity reactions (uncommon)

Essentially the same as for penicillins, exception is the monobactam

Cross-reactivity is possible, exception is the monobactam


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The End?

Nope.


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