Tulane Med Pharm Block 2

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broad spectrum microbials

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important for treating acute life threatening disease but disrupt normal microbiota

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narrow spectrum microbials

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requires identification of pathogen testing for sensitivity; less disruptive to normal microbiota

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acquired resistance

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horizontal gene transfer and spontaneous mutations

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bacterial cell walls

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contain peptidoglycan and NAG and NAM

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bacteriostatic drugs

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inhibit bacterial growth; patient's defense must work to eliminate microbes

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bactericidal

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drug kills bacteria; sometimes only inhibitory

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combinations of antibiotics that are neither synergistic or antagonistic

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additive

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cell wall inhibitors

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peptidoglycan synthesis, beta lactam, vancomycin, bacitracin

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Nucleic acid inhibitors

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fluoroquinones and rifamycins

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cell membrane integrity

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daptomycin and polymyxin B

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folate synthesis

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sulfonamides and trimethoprim

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have beta lactam ring

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cephalosporins, penicillins

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mechanism of beta lactams

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competitively inhibit enzymes that catalyze the formation of peptide bridges between adjacent glycan strands

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beta lactams

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only effective against actively growing cells

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mechanism of action of beta lactam

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bind to transpeptidase enzymes called penicillin binding proteins

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Vancomycin

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binds to the amino acid chain of NAM molecules blocking peptidoglycan synthesis

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bacitracin mechanism

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interferes with the transport of peptidoglycan precursors across the cytoplasmic membrane

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synthesized by some bacteria that breaks the beta lactam ring

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beta lactamase

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prevents peptide bonds from being formed

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chloramphenicol

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prevent the continuation of protein synthesis

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macrolides

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block the attachment of tRNA to the ribosome

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tetracylcines and glycyclines

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tetracycline mechanism of action

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reversibly bind to 30S subunit and prevent translation; actively transported into prokaryotic cells

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Glycyclines

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tetracylcine analogues; similar mechanism of action but wider activity and effective against many bacteria resitant to tetracyclines

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often drug of choice for patients allergic to penicillins

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macrolides

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inserts into the cytoplasmic membrane of Gram positive bacteria

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daptomycin

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most potent of penicillins

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Pen G

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administration of pen G

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IV or intramuscular because sensitive to stomach acid

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general characteristic of penicillins

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narrow spectrum and act against gram positives and few gram negatives

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resistant to most pencillinase and beta lactamases

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methicillin, cloxacillin, dicloxacillin, oxacillin

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antistaphylococcal penicillins

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very narrow spectrum; s aureus and s epidermis

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broad spectrum against gram negative and gram positive

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aminopenicillins

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have greater activity against pseudomonas

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extended spectrum

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enhanced penetration through cell wall and greater activity against gram negative

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extended spectrum

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not used in treatment of gram positive due to reduced activity

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extended spectrum penicillins

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substantially weaker than penicilin G and destroyed by many beta lactamases

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extended spectrum pencillins

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beta lactamase inhibitors

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clavulanic acid, sulbactam, tazobactam

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interstitial nephritis

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methicillin naficilin

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grouped into generations based on their spectrum of antimicrobial activity

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cephalosporins

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have true broad spectrum activity

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4th generation cephalosporin

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have relatively narrow spectrum of activity focused mainly on gram positive cocci

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1st generation cephalosporins

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most commonly used 1st generation cephalosporin

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Cefazolin

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do not penetrate well into the CSF and are not good for CNS infections

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1st generation cephalosporins

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second generation cephalosporins

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comparable to 1st generation cephalosporins against streptococci and gram positive cocci; gram negative aerobes and NO efficacy against pseudomonas and eterococci

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not used in the treatment of CNS infections because they do not cross the BBB

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2nd generation cephalosporins

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useful for mixed anaerobic and aerobic infections

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cephamycins

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marked activity against gram negative (penetration) and beta lactamase stability

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3rd generation cephalosporins

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two third generation cephalosporins with antipseudomonal activity

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ceftazidime, cefoperazone

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active against gram negative enterobacteriaceae but poorly active against gram positive cocci

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3rd generation cephalosporin

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broadest spectrum of activity of cephalosporins

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4th generation

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used primarily for nosocomial infections

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4th generation cephalosporins

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penetrates the CNS and can be used for treatment of encephalitis

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Cefepime

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activity against MRSA/ VRSA and only beta lactam with MRSA activity and also enterococcus infections

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Ceftaroline

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MRSA/E broadspectrum, gram + cocci likely won't reach US market

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Ceftobripole (Zeftera)

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cephalosporins are not generally recommended for patients who are

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immediate allergic reactions to penicillins; anaphylaxis and bronchospasms

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3rd and 4th generation of use of cephalosporins

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dissimilar to side chains with penicillin carries negligible risk of cross allergy

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resist beta lactamases

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carbapenems, monobactams, cell wall synthesis

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antibiotics of last resort , gram negative and gram positive and anaerobes

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carbapenems, monobactams,

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work only against gram negative aerobic bacteria like pseudomonas

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monobactam

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monobactams and penicillins

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no cross hypersensitivity

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often a drug of last resort used to treat Gram positive resitant to beta lactams and severe Clostridium difficile

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vancomycin

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toxicities of vancomycin

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can be nephrotoxic and ototoxic and thrombocytopenia

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non beta lactam inhibitors

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vancomycin and bacitracin

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limited to topical formulations because of toxicity

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bacitracin

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inhibits peptidoglycan precursor transport across the membrane and used in gram positive and negative skin infections

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bacitracin

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block the initiation of translation and cause misreading of mRNA

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Aminoglycosides

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interfere with the initiation of protein synthesis

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oxazolidinones

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treatment of infections for tetracycline

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spirochetal infections, rickettsia, chlamydia

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side effects of tetracycline

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hepatotoxic, photoxicity, and Fanconi syndrome

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only approved glycyclines

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tigecycline; wider activity and more active when bacterium are resistant to tetracyclines

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irreversibly bind to 30S subunit blocks initiation of translation

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Aminoglycosides

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category D drug for pregnancy risk

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aminoglycosides

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display bactericidal activity against aeorbes and can be used for some mycobacteria

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aminoglycosides

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macrolides

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azithromycin, clarithromycin, dirithromycin, roxithromycin, erythromycin, and telithromycin

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mechanism of macrolides

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reversibly bind to 50s ribosomal subunit

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often drug of choice for patients allergic to penicillin

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macrolides

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potent inhibitors of CYP3A4

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macrolides

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macrolide that does not inhibit CYP3A4

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Azithromycin

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macrolides that have class effect of QT prolongation which can lead to torsade de pointes

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erythromycin and clarithromycin

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chloramphenicol

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protein synthesis inhibtors; bacteriostatic and binds to 50s ribosomal subunit and blocks translation

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large apparent volume of distribution

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chloramphenicol

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lethal side effect of chloramphenicol

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aplastic anemia

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associated with IV administration of chloramphenicol

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gray baby syndrome

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adverse effects of chloramphenicol

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hypotension and cyanosis

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treatment of bacterial conjunctivitis

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chloramphenicol with topical ointments and eye drops

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lincosamides

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lincomycin and clindamycin

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used against TSS

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lincosamides

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risk of developing c difficile infections

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lincosamides

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oxazolidinones

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Linezolid, posizolid, tedizolid

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IV linezolid linox

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excellent bioavailability

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bind two sites of 50S ribosome

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Streptogramin A and B

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inhibit topoisomerase

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fluorquinones

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often used for genitourinary infections and nosocomial infections associated with urinary catheters

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fluorquinones

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contraindicated in a patient with QT prolongation, CNS lesions of inflammation or stroke

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fluoroquinones

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dual action slows the development of resistance

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4th generation fluorquinones

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mechanism of rifamycins

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inhibition of DNA dependent RNA synthesis; high affinity for the prokaryotic RNA polymerase

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rifamycins

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bactericidal against gram positves, some gram negatives

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major addition to the cocktail drug treatment of tuberculosis PIERS (pyrazinamide, isoniazid, ethambutol, streptomycin)

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rifamycin

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anaerobic activity is required to convert to its active form

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metronidazole

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used as an amoebicide antiprotozoal

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metronidazole

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high rates of metronidazole can cause

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steven johnson'syndorome and toxic epidermal necrolisis

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drug of choice for trichomonas vaginalis and bacterial vaginosis and mild to moderate c diff infection

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metronidazole

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can cause thrombocytopenia by lowering folic acid levels

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Trimethoprim

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drugs that interfere with folic acid synthesis

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trimethoprim and sulfonamide

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primary use of folic acid synthesis inhibitors

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urinary tract infections

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commonly used in a 1:5 combination with sulfamethoxazole

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trimethoprim

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inserts into the cytoplasmic membrane of gram positive bacteria and is usually uncommon to resistance so it can be used against other antib

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daptomycin

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primary use of daptomycin

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treatment of gram negative infections

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bind to the cell membrane of gram negative bacteria

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polymyxin b

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used in topical preparations of neosporin

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polymyxin B

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toxicities of polymyxin b

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neurotoxic, acute renal tubular necrosis

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uses of treatment of polymyxin b

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meningitis and UTIs

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1st line antibiotics for mycobacerium infection

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ethambutol, isoniazid, streptomycin, pyrazinamide, rifampicin

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inhibits mycolic acid syntheis

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isoniazid

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inhibits enzymes required for cell wall components

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ethambutol

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2nd line defense for mycobacterium

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aminoglycosides fluoroquinones; more toxic less effective and used for resistant strains

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frequent cause of neuropathy

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isoniazid

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causes thrombocytopenia

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rifampin

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third line of drugs for mycobacterium

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doubtful use and unproven efficacy ( clarithromycin, rifabutin, macrolides, linezolid)

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PIERS group of 5 medications preferred

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rifampin, pyrazinamide,isoniazid, ethambutol, streptomycin

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produces more extensive array beta lactamases

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gram negative

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beta lactamase inhibitors +penicillins

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suicide inhibitors; irreversibly bind to beta lactamase; enzyme remains acylated

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metabolic alkalosis

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ticarcillin

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newer generation of cephalosporins

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more gram negative and e and greater half lives so lower dosing rates

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1st generation cephalosporins

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cephaflecexin, cefazolin, cephalothin, cephadrine, cephaloridine, cephapirin, cefazedone, and cefadroxil

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2nd generation cephalosporins

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cefaclor, cefamandole, cefprozil, cefuroxime

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3rd generation cephalosporins

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cefcapene, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefoperazone, cefotaxime, cefpiramide, ceftizoxime, ce

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3rd generation cephalosporins antipseudomonal

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cefadizime cefaperazone

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covered by 3rd generation

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enterobacteriaceae

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4th generation cephalosporin can penetrate CSF and treat meningitis

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cefeprime

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VanA gene

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regulated by membrane associated kinase Van S

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vancomycin resistance phenotypic changes

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thicker cell wall, decrease cell wall turnover, trap glycopeptides, extra residues of d-alanine and alynyl

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lipopeptide

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daptomycin; binds to cell membrane of gram positive organisms does not cross membrane; calcium dependent;channels formm

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daptomycin resistant strains /higher MICS phenotypic changes

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enhanced membrane fluidity, decreased daptomycin binding, net positive surface charge and reduction of subsequent depolarization and cell autolysis

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daptomycin toxicities

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myalgias, skeleta muscle weaknes, elevated CPK that is reversible ; caution with statins for associated muscle toxicities

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daptomycin resistance

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mprf-gene contributes to membrane charge

yycg histidine kinase with multiple functions effects on membrane fatty acid synthesis

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linezolid

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inhibitors of protein synthesis; bacteriostatic

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mechanism of oxazolidinones

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bind at the interface of 50/30S ribosomes and prevent formation of 70 S complex

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major cause of linezolid resistance in VRE and MRSE

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23 S mRNA mutations and resistance without prior exposure to linezolid has been described

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quinolones mechanism

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topoisomerase and DNA gyrase inhibitors; cleavage of DNA

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resistance of quinolones

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genes for enzymes gryase and topoisomerase

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qnr genes

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protect from quinolone action against DNA gyrase and topoisomerase

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efflux pumps ( plasmids)

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quinolones

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quinolones toxicity

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GI intolerance, CNS, candida vaginitis, C . difficile colitis, and tendon rupture and photosensitivyt and toxicity, QT prolongation K channel block

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metronidazole

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low MW, prodrug, and cytotoxicity is from production of free radicals

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metronidazole resistance

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reduction in pyruvate; ferrodoxin oxidoreductase activity and decreased uptake of metronidazole

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acquisition of resistance of metronidazole

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mutational inactivation frxA NADPH, and fdxB

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h pylori resistance to metronidazole

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reductase encoding genes ( mutations)

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aminoglycosides

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require aerobic energy to bind to ribosomes and inhibit them

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Two steps of binding

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EDP-1 slow energy independent in the cytosol

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rapid EDP-2 represents binding to the ribosome

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aminoglycoside

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how aminoglycoside causes cell death

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abberrant protein, mRNA mistranslation and high concentration trapping of drug

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bacteria that are intrinsically resistant to aminoglycosides

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anaerobic

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acquired resistance of aminoglycosides

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decreased uptake, efflux pump activity, enzymatic modication of the drug

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mechanism of erythromycin

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inhibits RNA dependent protein synthesis @ chain elongation; blocking polypeptide exit tunnel and tRNA is dissociated from ribosome

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pattern of resistance MLSB ( macrolide, lincosamide, streptogramin B mediated by

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ERM genes on plasmids ( erythromycin ribosome methylation)

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overlapping binding site of the 50s ribosome with lincosamides

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macrolides and chloramphenicol

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mechanism of action of clindamycin

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protein synthesis is inhibited in early elongation interference with transpeptidation rxn

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D test

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s. aureus macrolide resistance MLSB resistance mechanism

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edge of clindamycin is closest to erythromycin disk and flattened like a D

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isolate resistant to clindamycin

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toxicities of Clindamycin

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stevens johnson, GI upset, diarrhea, C. diff colitis

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tetracyline use

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allergies to macrolides and beta lactams

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aminoglycosides

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category D for pregnancy

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used synergistically with beta lactams

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aminoglycosides; active transport uptake

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inhibitors of CYP3A4

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macrolides except Azithromycin

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therapeutics of lincosamides

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TSS and bacterioides fragilis

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risk of developing c diff

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lincosamides ( clindamycin)

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Synercid

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streptogramin a and b: bactericidal when combined

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third generation fluoroquinones

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active against streptococci

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dual action slows development of resistance

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4th generation quinolones

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Rifamycins

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nucleic acid synthesis inhibitor; bactericidal, mycobacteria

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strong affinity for prokaryotic RNA polymerase

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rifamycins (rifampin)

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rifampin

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mycobacteria; cocktail PIERS drug

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anaerobic metabolism required to convert drug to the active form

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metronidazole

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uses of metronidazole

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bacterial vaginosis, trichomonas vaginalis, and moderate to mild c. diff infections

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primarily used in urinary tract infections

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sulfonamide and trimethorpim

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endocarditis

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daptomycin

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inhibits mycolic acid synthesis

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isoniazid

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second line for mycobacterium infection

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aminoglycosides and fluoroquinones

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rifampin

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thrombocytopenia; hepatotoxic

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safe during pregnancy

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penicillins, cephalosporins, erythromycin

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enterococcus best treated with

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ampicillin

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beta lactamase stability

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monbactams and carbapenems

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action of carbapenems

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gram negative, positive, anaerobes

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only active against gram negative such as pseudomonas

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monobactams (Aztreonam)