Antibacterial Antibiotics Continued Flashcards Preview

Pharmacotherapeutics I > Antibacterial Antibiotics Continued > Flashcards

Flashcards in Antibacterial Antibiotics Continued Deck (62):
1

Antibacterial Agents

Interfere with protein synthesis by:
Interaction with bacterial ribosomes
Block initiation
Inhibition of tRNA synthesis
Multiple mechanisms leading to disruption of RNA processing

2

Direct binding to 50S substrate

Drug blocks binding of aminoacyl moeity of charged tRNA molecule to acceptor site of complex.
Drug prevents translocation of peptidyl tRNA from acceptor site to donor site on the 50S ribosomal subunit

3

Direct binding to 30S subunit

Drug blocks binding of amino acid charged tRNA to acceptor site of ribosomes mRNA complex
Drugs can block formation of initiation complex b/w ribosomes and mRNA, misread mRNA, block translocation of mRNA.

4

Protein synthesis inhibitor class may be "-static" or "-cidal" depending on?

Drug concentration
Site of infection
Infecting organism
ie. linezolid is -static for enterococi and staph but -cidal for strept

5

Aminoglycosides

Basic structure= aminocyclitol ring
Different side groups; different glycosidic linkages.

6

Aminoglycosides- 2 effects on bacterial cell resulting in death

Bind (-) charges in outer phospholipid membrane displacing cations that link phospholipids together resulting in disruption of wall and leakage of contents
Irreversibly disrupt protein synthesis by blocking initiation, misreading mRNA, blocking translocation.

7

Aminoglycosides gain access to the cell membrane how?

Via porin channels
Inhibited by acidic pH and anaerobic conditions
Enhanced by cell wall active ABX (synergism)

8

3 known mechanisms of resistance

Modification of aminoglycoside molecule by enzyme
Binding of aminoglycosides on rRNA altered
Reduced uptake of aminoglycosides.
To combat resistance use agents that target cell wall in conjunction w/ aminoglycosides.

9

Aminoglycosides- spectrum of activity

Active against aerobic gram-negative bacilli (klebsiella species, enterobacter, psudeomonas aeruginosa)
Little activity against anaerobes due to lack of stability
Tx- UTI, respiratory tract, skin and soft-tissue infections

10

Aminoglycosides- combination w/ other agents

To broaden coverage in serious illness (bacteremia or sepsis and psuedomonal infections)
For synergism w/ vancomycin or penicillins in the tx of endocarditis

11

Aminoglycosides- spectrum of activity

Exhibit concentration-dependent killing and have a pronounced post-antibiotic effect

12

Aminoglycosides- streptomycin

Useful in treating enterococcal infections

13

Aminoglycosides- gentamicin, tobramycin, amikacin

Most widely used Aminoglycosides.
Cross-resistance b/w these drugs

14

Aminoglycosides- Neomycin, kanamycin

Limited to oral or topical due to neprhotoxicity

15

Aminoglycosides-Spectinomycin

Structurally related to Aminoglycosides but lack amino sugars and glycosidic bonds. Used to tx for gonorrhea in PCN allergy patients.

16

Aminoglycosides- Adverse Effects

otoxicity- may be irreversible (sterptomycin is the most ototocix; not reported w/ genatamicin)
Nephrotoxicity- usually reversible

17

Aminoglycosides- Adverse Effects Neuromuscular blockage

Aggravate muscle weakness; respiratory paralysis in myasthenia gravis or Parkinson's disease due to curare-like effect

18

Aminoglycosides- hypersensitivity

Hypersensitivity rxn not common (rash, fever, urticaria, angioneurotic, edema, eosinophilia)

19

Aminoglycosides- Rare reactions

Optic nerve dysfunction, peripheral neuritis, encephalopathy, pancytopeniam exfoliative, dermatitis, amblyopia

20

Aminoglycosides- Adverse Effects tobramycin

Bronchospam and hoarseness with inhalation solution

21

Aminoglycosides- streptomycin

Contains metabisulfits avoid in sulfite allergies.

22

Aminoglycosides Phamacokinetics

No oral absportion (parenteral administration)
Widley distributed in ECF
Insoluble in lipid
Poor distribution in bile, aqueous humor, bronchial secretions, sputum, CSF
Clearance is proportional to creatinine clearance.

23

Gentamicin Dosing Strategies

Once daily dosing- Recommended for most clinical situations. Exclusion of Gram (+) infections, CrCl<30 ml/min, CF, spinal cord infections and burn patients
Multiple daily dosing- smaller amounts more times a day

24

Aminoglycoside drug interactions

Increased nephrotoxicity w/ loop diuretics
Respiratory depression when given w/ non-depolarizing muscle relaxants
Neomycin effects digoxin levels

25

Aminoglycosides- special populations-Category D

Amikacin, streptomycin, tobramycin, kanamycin

26

Aminoglycosides- special populations-Category C

Gentamicin, neomycin (minimal absorption of PO dose)

27

Aminoglycosides- special populations Breastfeeding

American academy of pediatrics (AAP) compatible

28

Tetracyclines- Semisynthetic

Tetracycline
Doxycycline
Minocycline

29

Tetracycline- broad spectrum

Gram (+), gram (-), aerobic and anaerobes.
Mycoplasma pneumoniae. chlamydia, rickettsia, borrelia burgdorferi, inflammatory acne, sinusitis, inhalation anthrax,
Concern for opportunistic infections

30

Tetracyclines- 3 groups based on PK traits

Short acting- Oxytertracycline, tertracycline (frequent dosing needed)
Intermediate acting- demeclocycline (Tx of SIADH)
Long acting- doxycycline and minocycline (BID dosing)

31

MOA of tetracycline

Inhibit protein synthesis by reversibly binding to the 30 S subunit of RNA

32

Tetracycline resistance

Bacterial efflux pump is the most important mechanism
Mutations that prevent entrance of TCN into the cell cause resistance.

33

Tetracyclones ROA and ADRs

Oral, parenteral, and ophthalmic
GI- N/V/D most common, Modified GI flora can develop candidiasis C diff
Bony-structures and teeth- binds to newly formed/forming bones and teeth
Photosensitization
Vestibular rxns- dizziness, vertigo
Pseudotumor cerbri
Lupus like rxn

34

Tertracyclines- pharmacokinetics

Absorption- Incomplete absorption from GI, impaired further by concurrent ingestion (Dairy, aluminum, Ca2+, Mg2+, iron, zinc, bimuth subsalicylates)
Distribution- throughout the body including meninges, accumulation in the liver, spleen, bone marrow, bone, and enamel of unerupted teeth
Elimination- mostly kidneys (except doxycycline through hepatic)

35

3rd Generation TCN- Tigecycline (tygacil)

Broad spectrum antimicrobial activity including MRSA
Indicated for tx of complicated intra-abdominal infections and complicated skin and skin structure infections in adults
Develped to overcome bacterial resistance mechanisms to TCNs

36

Chloramphenicol

50S inhibitor
Broad spectrum- gram (+), gram (-)
Due to blood dyscrasias it is reserved for life threatening infections such as typhoid fever, RMSF, and meningitis in pts allergic to PCN

37

Chloramphenicol- MOA

Both bactericidal and bacteriostatic depending on bacterial species
Reversibly binds 50S inhibiting formation of peptide bonds
Inhibits mitochondrial protein synthesis in mammalian cells
Broad tissue distribution, CNS and CSF.

38

Chloramphenicol- contraindications

very limited use- never in neonates or pregnant women

39

Chloramphenicol-ADRs

Myelosuppression
Reversible anemia
Neutropenia and thrombocytopenia
Gray baby syndrome in neonates (pallor, abd distention, vomiting, and collapse)

40

Chloramphenicol resistance

Plasmid born
decreased cellular permeability
Modification of enzymes- acetyltransferases
Mutation leading to ribosomal insensitivity

41

Macrolides

50S inhibitors
Erythromycin
Semisynthetic derivatives:
Clarithromycin and Azithromycin

42

Macrolides- MOA

Inihibit protein synthesis by binding to 50 S ribosomal unit, blocking translocation and preventing peptide elongation
Bacteriostatic; at high concentrations or with rapid bacterial growth -> bactericidal

43

Macrolides- spectrum of activity

Erythromycin is effective against most gram (+) bacteria and spirochetes (Legionella pneumophila, N gonorrhoeae, N meningitidis) poor anaerobic coverage
Clarithromycin- active against gram (+) and anaerobic bacteria (H. influenzae, H. pylori, mycobacterium avium)
Azithromycin- as above with anaerobic coverage.

44

Macrolides-resistance

H. Influenzae resistant to erythromycin alone, susceptible in combo with sulfonamide
Resistance is usually plasmid mediated.

45

Erythromycin Pharmacokinetics

Erythromycin base is destroyed by stomach acid and must be administered as enteric coated tablet or capsule.
Widely distributed including prostate and macrophages
Available PO, IV, and ophthalmic
Erythro, azithro excreted unchanged in bile
Clarithromycin excreted unchanged in bile and urine

46

Erythromycin Adverse Effects

GI- N/V/D and cramps, binds to motilin reveptor and increased peristalsis
Cholestatic jaundice (most common with estolate salt form)
CV- concern w/ macrolide ABX IV
Ventricular arryhtmias (Erythro), palpitations, CP, Dizziness, HA, IV- QT prolongation

47

Semisynthetic Macrolides- Clarithromycin (Biaxin)

Spectrum of activity = to erythromycin + enhanced coverage of atypical mycobacteria.
Less GI upset and BID dosing
ADRs- N/D, abnormal taste, dyspepsia, HA, tooth discoloration, transient anxiety and behavioral changes

48

Semisynthetic Macrolides- Azithromycin (Zithromax)

Spectrum of activity- atypical mycobacterial and heamophilus influenza coverage
Great tissue penetration and pronlonged intracellular 1/2 life
Angioedema

49

Macrolide Drug Interactions

Extensive
Erythro and clarithromycin= CYP3A4 substrates and inhibitors (erythro and clarithromycin are contraindicated w/ current use of cisapride. many interactions that increase/decrease effect- statins, ergots, dixogin, cabamezepine, warfarin)
Azithromycin NOT metabolized by CYP3A4

50

Ketolides

New gen of macrolide ABX
Semi-synthetic derivative of erythromycin
Higher binding affinity to 50S subunit
DIsplays greater potency against gram (+) organisms
Displays activity against macrolide-resistant strains

51

Telithromycin (Ketek)

Tx of respiratory tract infects in 2004
Tx of CAP, sinusitis, bronchitis
Feb 2007 dropped chronic bronchitis and sinusitis
2006 black box linked to liver failure and death

52

Telithromycin (Ketek)

Hepatic metabolism w/ elimination in bile and urine
ADRs- N/D, HA, Dizziness, V, reversible LFT elevation, hepatitis, reversible blurred vision, diplopia, exacerbation of myasthenia gravis, and QT prolongation

53

Lincosamides: Clindamycin (cleocin)

Inhibits protein synthesis
Spectrum of activity- gram (+)- strep, staph, pneumococci, anaerobes = gram (+) and (-) except C diff
Available oral, IV, and topical

54

Clindamycin (cleocin)- clinical uses

Tx of anaerobic or mixed (polymicrobial infections)
Perforated viscus, infections of the female GU tract, decubitis, venous stasis, or arterial insufficiencyulcers
Aspiration pneumonia
Mild inflammatory acne- topical

55

Clindamycin (cleocin)- Adverse effects

Gi-N/V/D
Hepatotoxicity
Neutropenia
Most common ABx to cause Clostridium difficile toxin mediated to diarrhea

56

Streptogramins: Quinupristin Dalfopristin (Synercid)

Inhibit protein synthesis
Bacteriostatic
Indications- life threatening infections associated with VRE bactermia
Tx of complicated skin/structure infections by Methicillin-suspeptible S aureus or S. pyrogenes

57

Quinupristin Dalfopristin (Synercid)

P450 3A4 inhibitor (nifedipine, cyclosporin drug interactions)
IV only, limited tissue distribution, metabolized in the liver to active metabolites

58

Quinupristin Dalfopristin (Synercid) ADRS

Phelbitis, arthralgias, myalgias, hyperbilirubinemia

59

Ozazolidinones: Linezolid (Zyvox)- indications

Vanco-resistant enterococcus faecium (VRE), nosocomial pneumonia due to S aureus including MRSA or S. pneumoniae; complicated/uncomplicated skin/structure infections; gram (+) CAP

60

Ozazolidinones: Linezolid (Zyvox)- MOA

Prevents function of initiation complex
Mechanism distinct from other 50S ribosomal inhibitors -> active bacteria that is resistant to other protein synthesis inhibitors.

61

Linezolid

Bacteriostatic against enterococci and staph; bactericidal against strept
Oral and IV preps available
Metabolized by non-P450 enzymes, excreted in urine

62

Linezolid- ADRs

GI, HA, thrombocytopenia, linezolid=MAOI-> HTN if used with adrenergic and serotonergic drugs