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Term 5 Flash Cards > Antimicrobials > Flashcards

Antimicrobials Flashcards

1
Q

Cell wall synthesis inhibitors

A

B-lactam antibiotics, vancomycin, daptomycin, bacitracin & fosfomycin

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2
Q

Protein synthesis inhibitors

A

tetracyclines, glycylcyclines, aminoglycosides, macrolides, chloramphenicol, clindamycin, streptogramins & linezolid

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3
Q

Drugs that affect nucleic acid synthesis

A

fluoroquinolones, sulfonamides & trimethoprim

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4
Q

Miscellaneous and urinary antiseptics

A

metronidazole & nitrofurantoin

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5
Q

Penicillins

A

• Inactive against organisms without peptidoglycan cell wall eg, mycoplasma, protozoa, fungi, viruses

Autolysin production
• Produced by bacteria and mediate cell lysis
• Penicillins activate autolysins to initiate cell death
• Bacteria eventually lyse due to activity of autolysins and inhibition of cell-wall assembly

Ability to ‘reach’ PBPs determined by:
• size
• charge
• hydrophobicity

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6
Q

Penicillin G

A

• Benzylpenicillin

Active against:
• Most Gram-positive cocci (NOT Staph)
• Gram-positive rods (eg, Listeria, C.perfringens)
• Gram-negative cocci (eg, Neisseria sp)
• Most anaerobes (NOT bacteroides)
• Susceptible to inactivation by B-lactamases

Drug of choice for:
• Syphilis (benzathine penicillin G)
• Strep infections (especially in prevention of rheumatic fever)
• Susceptible pneumococci

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7
Q

Repository penicillins

A

• Developed to prolong duration of penicillin G

Penicillin G procaine
• IM not IV (risk of procaine toxicity)
• t1/2 = 12-24h
• Seldom used (increased resistance)

Penicillin G benzathine
• IM
• t1/2 = 3-4 weeks
• DOC for syphilis, rheumatic fever

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8
Q

Penicillin V

A
  • Similar antibacterial spectrum to penicillin G (LESS ACTIVE against Gram –ve bacteria)
  • More acid stable than G (can give ORALLY)

Drug of choice for:
• Strep throat
• Employed mostly orally for mild-moderate infections eg, pharyngitis, tonsilitis, skin infections (caused by Strep)

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9
Q

Antistaphylococcal penicillins

A
  • Methicillin, Nafcillin, Oxacillin, Dicloxacillin
  • B-lactamase resistant
  • Inactive against MRSA
  • Restricted to treatment of B-lactamase-producing staphylococci
  • Recommended as first-line treatment for staphylococci endocarditis in patients without artificial heart valves
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10
Q

Extended spectrum

A
  • Ampicillin, Amoxicillin
  • Similar to penicillin G (also have Gram-negative activity)
  • Susceptible to B-lactamases
  • Activity enhanced with B-lactamase inhibitor
  • Amoxicillin has higher oral bioavailability than other penicillins (including ampicillin)
  • Amoxicillin is a common antibiotic prescribed for children and in pregnancy
  • Used for treatment of a number of infections: acute otitis media, streptococcal pharyngitis, pneumonia, skin infections, UTIs etc.
  • Widely used to treat upper respiratory infections (H.influenzae & S.pneumoniae)
  • Amoxicillin = standard regimen for endocarditis prophylaxis during dental or respiratory tract procedures

• Ampicillin is used in combination with aminoglycoside to treat Enterococci and Listeria infections

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11
Q

Antipseudomonal penicllins

A
  • Carbenicillin, Ticarcillin, Piperacillin
  • Effective against many Gram-negative bacilli
  • Often combined with B-lactamase inhibitor
  • Active against P.aeruginosa
  • Commonly used to treat Pseudomonas aeruginosa
  • Treatment of moderate-severe infections of susceptible organisms (eg, uncomplicated & complicated skin, gynecologic and intra-abdominal infections, febrile neutropenia)
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12
Q

Penicillin + aminoglycosides

A
  • Synergistic
  • Penicillins facilitate movement of aminoglycosides through cell wall
  • Should never be placed in same infusion fluid (form inactive complex)
  • Effective empiric treatment for infective endocarditis
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13
Q

Penicillin PK

A

Oral absorption
• Absorption impaired by food (except amoxicillin -> high oral bioavailability)
• Nafcillin = erratic (not suitable for oral admin.)

Distribution
• All achieve therapeutic levels in pleural, pericardial, peritoneal, synovial fluids & urine
• Nafcillin, ampicillin & piperacillin achieve high levels in bile
• Levels in prostate & eye = insufficient
• CSF penetration = poor (except in meningitis)

Excretion
• Most excreted primarily via kidney (beware in kidney failure)
• Nafcillin = exception as primarily excreted in bile
• Oxacillin & dicloxacillin = renal & biliary excretion

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14
Q

Penicillin SEs

A

Hypersensitivity
• Penicilloic acid = major antigenic determinant
• ~ 5 % patients claim to have some reaction
(maculopapular rash -> anaphylaxis)
• Cross-allergic reactions between B-lactam antibiotics can occur

  • GI disturbances (eg, diarrhea)
  • Pseudomembranous colitis (ampicillin)
  • Maculopapular rash (ampicillin, amoxicillin)
  • Interstitial nephritis (particularly methicillin)
  • Neurotoxicity (epileptic patients at risk)
  • Hematologic toxicities (ticarcillin)
  • Neutropenia (nafcillin
  • Hepatitis (oxacillin)
  • Secondary infections (eg, vaginal candidiasis)
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15
Q

B-lactamase inhibitors

A
  • Clavulanic acid, sulbactam, tazobactam
  • Contain B-lactam ring but do not have sig. antibacterial activity
  • Bind to and inactivate most B-lactamases
  • Available only in fixed combinations with specific penicillins
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16
Q

Cephalosporins

A
  • B-lactam antibiotics
  • Bactericidal
  • Same MOA as penicillins
  • Affected by similar resistance mechanisms
  • Classified into generations

• All cephalosporins are considered inactive against Enterococci, Listeria, Legionella, Chlamydia, Mycoplasma, and Acinetobacter species.

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17
Q

Cephalosporins first generation

A
  • Cefazolin, Cephalexin
  • Penicillin G substitutes
  • Resistant to staphylococcal penicillinase
  • Activity against Gram-positive cocci & P.mirabilis, E.coli, & K.pneumoniae
  • Rarely DOC for any infections
  • Cefazolin = DOC for surgical prophylaxis
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18
Q

Cephalosporins second generation

A
  • Cefaclor, Cefoxitin, Cefotetan, Cefamandole
  • Extended Gram-negative coverage
  • Greater activity against H.influenzae, Enterobacter aerogenes and some Neisseria species
  • Weaker activity against Gram-positive organisms
  • Primarily used to treat sinusitis, otitis & lower respiratory tract infections
  • Cefotetan & cefoxitin = prophylaxis & therapy of abdominal and pelvic cavity infections
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19
Q

Cephalosporins third generation

A
  • Ceftriaxone, Cefoperazone, Cefotaxime, Ceftazidime, Cefixime
  • Enhanced activity against Gram-negative cocci
  • Highly active against enterobacteriacae, Neisseria, & H.influenzae
  • Less active against most Gram-positive organisms
  • Cefotaxime & ceftriaxone = usually active against pneumococci
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20
Q

Ceftriaxone

A
  • Third generation cephalosporins
  • DOC for gonorrhea
  • DOC for meningitis due to ampicillin-resistant H.influenzae
  • Prophylaxis of meningitis in exposed individuals
  • Treatment of Lyme disease (CNS or joint infection)
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21
Q

Cefaperazone, Ceftazidime

A
  • Third generation cephalosporins

* Activity against P.aeruginosa

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22
Q

Cephalosoprins fourth generation

A
  • Cefipime
  • Parenteral admin. Only
  • Wide antibacterial spectrum
  • Gram +ve activity of 1st generation + Gram -ve activity of 3rd generation
  • eg, enterobacter, Haemophilis, Neisseria, E.coli, pneumococci, P.mirabilis & P.aeruginosa

• Treatment of infections with susceptible organisms eg, UTI’s, complicated intra-abdominal infections, febrile neutropenia

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23
Q

Cephalosporins fifth generation

A
  • Ceftaroline
  • Parenteral admin. Only
  • Only cephalosporins with activity against MRSA
  • Similar spectrum of activity to 3rd generation
  • eg, enterobacter, Haemophilis, Neisseria, E.coli, pneumococci, P.mirabilis & P.aeruginosa

• Considering its spectrum of activity, including MRSA, ceftaroline is useful in the treatment of skin and soft tissue infection due to this pathogen, particularly if gram-negative pathogens are coinfecting.

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24
Q

Cephalosporlins PK

A
  • Most administered parenterally (exceptions = cephalexin, cefaclor, cefixime)
  • 3rd generation only reach adequate levels in CSF
  • Mainly eliminated via kidneys (exceptions = ceftriaxone & cefoperazone excreted in bile)
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25
Q

Cephalosporins SEs

A

• Allergic reactions (cross-sensitivity with penicillins can occur)
However, minor penicillin allergic patients often treated successfully with a cephalosporin
• Pain at infection site (IM), thrombophlebitis (IV)
• Superinfections (eg, C.difficile)

  • Cefamandole, cefoperazone & cefotetan contain methyl-thiotetrazole group, all can cause:
  • hypoprothrombinemia (Vit. K1 admin can prevent) &
  • disulfiram-like reactions (avoid alcohol)
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26
Q

Carbapenems

A
  • Imipenem, Meropenem. Synthetic B-lactam antibiotics
  • Resist hydrolysis by most B-lactamases
  • Very broad spectrum of activity
  • Active against penicillinase-producing Gram-positive & negative organisms; aerobes & anaerobes; P.aeruginosa
  • Not active against carbapenemase producing organisms eg, carbapenem-resistant enterobacteriaceae, carbapenem-resistant klebsiella
  • Not active against MRSA

Drugs of choice for
• enterobacter infections
• extended-spectrum B-lactamase producing Gram-negatives

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27
Q

Carbapenem PK and SEs

A

PK
• IV
• Imipenem forms potentially nephrotoxic metabolite. Combining with enzyme inhibitor Cilastatin prevents metabolism thus prevents toxicity & increases availability.
• Meropenem is not metabolized by same enzyme (no need for Cilastatin)

SEs
• GI distress (nausea, vomiting, diarrhea)
• High levels of imipenem can provoke seizures
• Allergic reactions (partial cross-reactivity with penicillins)

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28
Q

Monobactams

A
  • Aztreonam
  • Aerobic Gram-negative rods ONLY (including pseudomonas)
  • No activity against Gram-positive bacteria or anaerobes
  • Resistant to action of B-lactamases

• UTI’s, lower respiratory tract infections, septicemia, skin/structure infections, intraabdominal infections, gynecological infections caused by susceptible Gram- negative bacteria

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29
Q

Monobactam PK and SE

A
  • Mainly IV or IM
  • Can be given by inhalation in CF patients
  • Penetrates CSF when inflamed
  • Excreted primarily via urine

SE
• Relatively nontoxic
• Little cross-hypersensitivity with other

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30
Q

Vancomycin

A
  • Active against Gram-positive bacteria only
  • Virtually all Gram-negative organisms are intrinsically resistant
  • Effective against multi-drug resistant organisms (eg, MRSA, enterococci, PRSP)
  • Binds to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide
  • Inhibits bacterial cell wall synthesis & peptidoglycan polymerization

RESISTANCE
• Plasmid-mediated changes in drug permeability
• Modification of the D-Ala-D-Ala binding site (D-Ala replaced by D-lactate)

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31
Q

Vancomycin clinical applications

A
  • Treatment of serious infections caused by B-lactam resistant Gram +ve organisms eg, MRSA
  • Treatment of Gram +ve infections in patients severely allergic to B-lactams
  • In combination with an aminoglycoside for empirical treatment of infective endocarditis
  • In combination with an aminoglycoside for treatment of enterococcal endocarditis or PRSP
  • Given orally for the treatment of staphylococcal enterocolitis or antibiotic-associated pseudomembranous colitis (C.difficile)
32
Q

Vancomycin PK and SE

A
  • Poor oral absorption
  • Requires slow IV infusion (60-90 min)
  • Penetrates CSF when inflamed
  • 90-100% excreted via kidneys

SE
• Mostly minor eg, fever, chills, phlebitis at infusion site
• ‘Red man’ or ‘red neck’ syndrome (infusion-related flushing over face and upper torso)
• Ototoxicity (drug accumulation)
• Nephrotoxicity (drug accumulation)

33
Q

Daptomycin

A
  • Effective against resistant Gram-positive organisms (eg, MRSA (ORSA), enterococci, VRE & VRSA)
  • Recommended for treatment of severe infections caused by MRSA or VRE
  • Treatment of complicated skin/structure infections caused by susceptible S.aureus
  • Inactive against Gram-negative bacteria
  • Not effective in treatment of pneumonia
  • Novel mechanism of action -> useful against multi-drug resistant bacteria
  • Binds to cell membrane via calcium-dependent insertion of lipid tail
  • Results in depolarization of cell membrane with K+ efflux -> cell death
34
Q

Daptomycin PK and SE

A
  • IV only
  • Can accumulate in renal insufficiency

SE
• Constipation, nausea, headache, insomnia
• Elevated creatine phosphokinases (recommended to discontinue coadmin. of statins)

35
Q

Bacitracin

A
  • Unique mechanisms -> no cross resistance
  • Interferes in late stage cell wall synthesis
  • Effective against Gram-positive organisms
  • Marked nephrotoxicity
36
Q

Fosfomycin

A
  • Inhibits cytoplasmic enzyme enolpyruvate transferase in early stage of cell wall synthesis
  • Active against Gram-positive and negative organisms
  • Oral
  • Used for treatment of uncomplicated lower UTI’s
37
Q

Protein synthesis inhibitors

A
  • Tetracyclines
  • Glycylcyclines
  • Aminoglycosides
  • Macrolides
  • Chloramphenicol
  • Clindamycin
  • Streptogramins
  • Linezolid
  • Mupirocin
  • Bind to and interfere with ribosomes
  • Bacterial ribosome (70S) differs from mammalian (80S) but closely resembles mammalian mitochondrial ribosome
  • Mostly bacteriostatic
38
Q

Tetracyclines

A
  • Doxycycline, Minocycline, Tetracycline
  • Broad-spectrum
  • Bacteriostatic
  • Activity against many aerobic and anaerobic Gram- positive & Gram-negative organisms
  • Entry via passive diffusion & energy-dependent transport unique to bacterial inner cytoplasmic membrane
  • Susceptible cells concentrate drug intracellularly
  • Bind reversibly to 30S subunit of ribosome, preventing binding of aminoacyl tRNA
39
Q

Tetracycline resistance

A

• Widespread resistance (usually plasmid mediated)

  • 3 main mechanisms:
  • Impaired influx or increased efflux by active protein pump
  • Production of proteins that interfere with binding to ribosome
  • Enzymatic inactivation
40
Q

Tetracyclines

A

• Most common use = severe acne & rosacea
• Used in empiric therapy of community-acquired
pneumonia (outpatients)
• Can be used for infections of respiratory tract, sinuses, middle ear, urinary tract, & intestines
• Syphilis (patients allergic to penicillin)

Drugs of choice for: 
• Chlamydia
• Mycoplasma pneumoniae 
• Lyme disease
• Cholera
• Anthrax prophylaxis
• Rickettsia (Rocky Mountain Spotted Fever, typhus)

Used in combination for:
• H.pylori eradication
• Malaria prophylaxis and treatment
• Treatment of plague, tularemia, brucellosis

41
Q

Tetracycline PK and SE

A
  • Variable oral absorption (decreased by divalent & trivalent cations)
  • Doxycycline (lipid soluble) = preferred for parenteral admin. and good choice for STD’s and prostatitis
  • Minocycline = reaches high concentrations in all secretions (useful for eradication of meningococcal carrier state)
  • Concentrate in liver, kidney, spleen & skin
  • Excreted primarily in urine except doxycycline (primarily via bile)
  • TERATOGENIC – all cross placenta & are excreted into breast milk (FDA category D)

SE
• Gastric effects / superinfections (nausea, vomiting, diarrhea)
• Discoloration & hypoplasia of teeth, stunting of growth (generally avoided in pregnancy & not given in children under 8y)
• Fatal hepatotoxicity (in pregnancy, with high doses, patients with hepatic insufficiency)
• Exacerbation of existing renal dysfunction
• Photosensitization
• Dizziness, vertigo (esp. doxycycline & minocycline)

42
Q

Glycylcyclines

A
  • Tigecycline
  • Structurally similar to tetracyclines
  • Treatment of complicated skin, soft tissue and intra- abdominal infections

Antibacterial spectrum
• Broad-spectrum against multidrug-resistant Gram- positive, some Gram-negative & anaerobic organisms

RESISTANCE
• Little resistance
• Not subject to same resistant mechanisms as tetracyclines (exceptions = efflux pumps of Proteus & Pseudomonas species)

43
Q

Glycylcyclines PK and SE

A

PK
• IV only
• Excellent tissue & intracellular penetration
• Primarily biliary/fecal elimination

SE 
• Well tolerated
• AE similar to tetracyclines
Contraindications
• Pregnancy & children <8y
  • Increased risk of mortality has been observed with tigecycline compared with other antibiotics when used to treat serious infections
  • FDA recommends considering the use of alternative antimicrobials when treating patients with serious infections
44
Q

Aminoglycosides

A
  • Amikacin, Gentamicin, Tobramycin, Streptomycin, Neomycin
  • Bactericidal
  • Associated with serious toxicities
  • Largely replaced by safer antibiotics
  • Most active against aerobic Gram-negative bacteria
  • Anaerobes lack O2-dependent transport
  • Used mostly in combination
  • Empiric therapy of serious infections eg, septicemia, nocosomial respiratory tract infections, complicated UTI’s, endocarditis etc
  • Once organism is identified aminoglycosides are normally discontinued in favor of less toxic drugs

Drugs of choice for:
• Empiric therapy of infective endocarditis in combination with either a penicillin or (more commonly) vancomycin
• Streptomycin is the drug of choice for Plague (Y.Pestis)

  • Passively diffuse across membranes of Gram-negative organisms
  • Actively transported (O2-dependent) across cytoplasmic membrane
  • Bind to 30S ribosomal subunit prior to ribosome formation leading to:
  • misreading of mRNA, &
  • inhibition of translocation
45
Q

Aminoglycosides resistance

A

3 principal mechanisms:
• Plasmid-associated synthesis of enzymes that modify and inactivate drug
• Decreased accumulation of drug
• Receptor protein on 30S ribosomal subunit may be deleted or altered due to mutation

46
Q

Oral Neomycin

A

• Used as adjunct in treatment for hepatic encephalopathy

Alternative treatment options for hepatic encephalopathy:
• Lactulose
• Oral vancomycin
• Oral metronidazole 
• Rifaximin
47
Q

Lactulose

A

Other Effects
• Prebiotic (suppression of urase producing organisms)
• Osmotically active laxative

Adverse Effects
• Osmotic diarrhea
• Flatulence
• Abdominal cramping

48
Q

Aminoglycosides PK and SE

A
  • Parenteral admin. only (except neomycin - topical)
  • Once-daily admin.
  • Well distributed (excluding CSF, bronchial secretions)
  • High levels in renal cortex & inner ear
  • 99% excreted in urine (reduce dose in renal insufficiency)

SE
Both time- and concentration-dependent
• Ototoxicity
• Nephrotoxicity
• Neuromuscular blockade (myasthenia gravis = contraindicated)
• Pregnancy (contraindicated unless benefits outweigh risks – FDA Category D)

49
Q

Macrolides

A
  • Erythromycin, Clarithromycin, Azithromycin, Telithromycin
  • Mainly used to treat Gram-positive infections
  • Bacteriostatic (bactericidal at high conc.)
  • Most active against Gram-positive bacteria (some activity against Gram-negatives)
  • Spectrum is slightly wider than that of penicillins
  • Azithromycin, clarithromycin & telithromycin have broader spectrum than erythromycin
  • Used in empiric therapy of community-acquired pneumonia (outpatient & in combination with B-lactam for inpatients)
  • Treatment of upper respiratory tract & soft-tissue infections (eg, Staph, H.influenzae, S.pneumoniae, enterococci)
  • Erythromycin = DOC for whooping cough (B.pertussis)
  • Common substitute for patients with penicillin allergy
  • Reversibly bind to 50S subunit inhibiting translocation
  • Binding site is identical or close to that for clindamycin & chloramphenicol
50
Q

Macrolides resistance

A

3 main mechanisms (usually plasmid encoded):
• Reduced membrane permeability or active efflux
• Production of esterase that hydrolyze drugs (by enterobacteriaceae)
• Modification of ribosomal binding site (by chromosomal mutation or by a methylase)
• Complete cross-resistance between erythromycin, azithromycin, & clarithromycin
• Partial cross-resistance with clindamycin & streptogramins

51
Q

Macrolides PK, SE, CI

A
  • Clarithromycin, azithromycin, telithromycin = improved oral absorption, longer t1/2, increased bioavailability compared to erythromycin
  • Azithromycin & telithromycin = greater tissue penetration compared to other macrolides
  • Erythromycin, clarithromycin & telithromycin = CYP P450 inhibition (NOT azithromycin)

SE
• GI irritation
• Hepatic abnormalities (erythromycin & azithromycin)
• QT prolongation
• Severe reactions are rare (anaphylaxis, colitis)

CI
• Statins (due to macrolides inhibiting CYP P450)
• Telithromycin – fatal hepatotoxicity, exacerbations of myasthenia gravis, & visual disturbances -> don’t use for minor illnesses

52
Q

Chloramphenicol

A
  • Potent inhibitor of protein synthesis
  • Broad-spectrum (aerobic & anaerobic Gram-positive & - negative organisms)
  • Bacteriostatic (usually)
  • Toxicity limits use to life-threatening infections with no alternatives
  • Very broad spectrum
  • Activity against Gram-positive and negative bacteria, including Rickettisae & anaerobes
  • N.meningitidis, H.influenzae, Salmonella & bacteroides = highly susceptible
  • Never given systemically for minor infections (due to adverse effects)

• Serious infections resistant to less toxic drugs
• When chloramphenicols penetrability to site of
infection is clinically superior to other drugs
• Active against many VRE
• Topical treatment of eye infections (mainly outside US)

  • Enters cells via active transport process
  • Binds reversibly to 50S ribosomal subunit (site adjacent to site of action of macrolides & clindamycin)
  • Can inhibit protein synthesis in mitochondrial ribosomes -> bone marrow toxicity

RESISTANCE
• Presence of factor that codes for chloramphenicol acetyltransferase (inactivates drug)
• Changes in membrane permeability

53
Q

Chloramphenicol PK and SE

A
  • Oral, IV or topical
  • Wide distribution (readily enters CSF)
  • Inhibits hepatic oxidases (3A4 & 2C9)
SE
• GI distress
• Bone marrow depression:
• dose-related reversible depression
• severe irreversible aplastic anemia
• Gray baby syndrome (cyanosis), due to drug accumulation
54
Q

Clindamycin

A
  • MOA = same as macrolides (binds to 50S subunit)
  • Mainly bacteriostatic
  • Primarily used against Gram-positive anaerobic bacteria (including bacteroides)
  • Anaerobic infections (eg, bacteroides infections, abscesses, abdominal infections)
  • Skin and soft tissue infections (streptococci and staphylococci, and some MRSA)
  • In combination with primaquine as an alternative in PCP
  • In combination with pyrimethamine as an alternative in toxoplasmosis of brain
  • Prophylaxis of endocarditis in valvular patients allergic to penicillin
RESISTANCE
Due to:
• mutation of ribosomal receptor site 
• modification of the receptor
• enzymatic inactivation of drug
• Most Gram-negative aerobes & enterococci are intrinsically resistant
• Cross-resistant with macrolides
55
Q

Clindamycin PK and SE

A
  • Oral or IV
  • Good penetration (including abscesses and bones)

SE
• GI irritation (~ 20% people experience diarrhea)
• Potentially fatal pseudomembranous colitis
(superinfection of C.difficile)
• Skin rashes (~10 %)
• Neutropenia & impaired liver function

56
Q

Streptogramins

A
  • Quinupristin, Dalfopristin
  • Given as a combination (act synergistically to have bactericidal action)
  • Long postantibiotic effect
  • Gram-positive cocci
  • Multi-drug resistant bacteria (streptococci, PRSP, MRSA, E.faecium)
  • Restricted to treatment of infections caused by drug- resistant Staphylococci or VRE

Mechanism of action
• Bind to separate sites on 50S bacterial ribosome • Resistance is uncommon

57
Q

Streptogramins PK

A
  • IV only
  • Penetrates macrophages & polymorphonucleocytes
  • Inhibitors of CYP 3A4

SE
• Infusion related (venous irritation, arthralgia & myalgia)
• GI effects
• CNS effects (headache, pain)

58
Q

Linezolid

A
  • Bacteriostatic (cidal against streptococci & Clostridium perfringens)
  • Most Gram-positive organisms (staphylococci, streptococci, enterococci, Corynebacterium, Listeria monocytogenes)
  • Moderate activity against mycobacterium tuberculosis
  • Treatment of multi-drug resistant infections

Mechanism of action
• Inhibits formation of 70S initiation complex
• Binds to unique site on 23S ribosomal RNA of 50S subunit

RESISTANCE
• Decreased binding to target site
• No cross-resistance with other drug classes

59
Q

Linezolid PK, SE, CI

A
  • Oral (100% bioavailable) & IV
  • Widely distributed (including CSF)
  • Weak reversible inhibitor of MAO

SE
• Well tolerated for short admin. (GI, nausea, diarrhea, headaches, rash)
Long-term admin. can cause:
• Reversible myelosuppression
• Optic & peripheral neuropathy, & lactic acidosis

CI
• Reversible, nonselective inhibitor of MAO -> potential to interact with adrenergic and serotonergic drugs

60
Q

Fidaxomicin

A

• Narrow spectrum macrocyclic antibiotic
• Activity against Gram-positive aerobes and
anaerobes especially Clostridia
• No activity against Gram-negative bacteria
• Treatment of C.difficile colitis (in adults)

• Inhibits bacterial protein synthesis by binding to RNA polymerase

PK
• When administered orally, systemic absorption is negligible but fecal concentrations are high

SE
• Main effects appear to be gastrointestinal disorders
• The safety and effectiveness of fidaxomicin in patients < 18 years of age have not been established.

61
Q

Mupirocin

A

• Antibiotic belonging to monoxycarbolic acid class
• Activity against most Gram-positive cocci, including MRSA and most streptococci (but not enterococci)
• Only topical/intranasal agent with activity against MRSA
• Intranasal:
• Eradication of nasal colonization with MRSA in
adult patients and healthcare workers • Topically:
• Treatment of impetigo or secondary infected traumatic skin lesions due to S.aureus or S.pyogenes

• Binds to bacterial isoleucyl transfer-RNA synthetase resulting in the inhibition of protein synthesis

SE
• Resistance develops if used for long periods of time
• Mainly local and dermatologic effects (eg, burning, edema, tenderness, dry skin, pruritus)

62
Q

Fluoroquinolones

A
  • Broad spectrum, bactericidal drugs
  • Enter bacterium via porins
  • Inhibit bacterial DNA replication via interference with topoisomerase II (DNA gyrase) & IV
  • Classified into generations
  • Lower generations have excellent Gram-negative activity
  • Higher generations have improved activity against Gram- positives

RESISTANCE
• Emerged rapidly in 2nd generation (esp. C.jejuni, gonococci, Gram-positive cocci, P.aeruginosa & serratia).
• Due to chromosomal mutations that:
• encode subunits of DNA gyrase (eg, gonococci resistance) and topo IV
• regulate expression of efflux pumps (eg, S.aureus, S.pneumonia, M.tuberculosis)
• Cross-resistance between drugs occurs

63
Q

Fluroquinolones generations

A

1st - Nalidixic acid
• Moderate Gram -ve activity
• Uncomplicated UTI’s

2nd - Ciprofloxacin
•Expanded Gram -ve activity
• Some activity against Gram +ve and atypical organisms
• Synergistic with B-lactams
•Travelers diarrhea (E.coli)
• P.aeruginosa (CF patients)
• Prophylaxis against meningitis (alternative to ceftriaxone & rifampin)

3rd - Levofloxacin
• Expanded Gram -ve activity
• Improved activity against Gram +ve and atypical organisms
• Excellent activity against S.pneumoniae
• Prostatitis (E.coli)
• STD’s (not syphilis)
• Skin infections
• Acute sinusitis, bronchitis, TB Community acquired pneumonia

4th - Gemifloxacin, Moxifloxacin
• Improved Gram +ve activity and anaerobic activity
• Community acquired pneumonia

64
Q

Respiratory fluoroquinolones

A 
Levofloxacin, moxifloxacin & gemifloxacin (excellent activity against S.pneumoniae, H.influenzae & M.catarrhalis)
Used in treatment of pneumonia when:
• First-line agents have failed
• In the presence of comorbidities 
• Patient is an inpatient
65
Q

Fluoroquinolones PK and SE

A
  • Good oral bioavailability
  • Well distributed into all tissues and fluids (including bones)
  • Iron, zinc, calcium (divalent cations) interfere with absorption
  • Dosage adjustments required in renal dysfunction (except moxifloxacin)

SE
• GI distress
• CNS, rash, photosensitivity
• Connective tissue problems (avoid in pregnancy, nursing mother, under 18’s)
• QT prolongation (moxifloxacin, gemifloxacin, levofloxacin)
• High risk of causing superinfections (C.difficile, C albicans, streptococci)

66
Q

Fluoroquinolones interactions and CI

A
  • Theophylline, NSAIDs & corticosteroids = enhance toxicity of fluoroquinolones
  • 3rd & 4th generation = raise serum levels of warfarin, caffeine & cyclosporine
  • Pregnancy & nursing mothers
  • Children < 18y (unless benefits outweigh risks)
67
Q

Sulfonamides

A
  • Sulfamethoxazole, Sulfadiazine, Sulfasalazine
  • Structural analogs of p-aminobenzoic acid (PABA)
  • Bacteriostatic against Gram-positive & Gram-negative organisms
  • Infrequently used as single agents (resistance)
  • Topical agents (ocular, burn infections)
  • Oral agents (simple UTI’s)
  • Sulfasalazine (oral) = ulcerative colitis, enteritis, IBD
  • Inhibit bacterial folic acid synthesis
  • Synthetic analogs of PABA (p-amino-benzoic acid)
  • Competitive inhibitors (& substrate) of dihydropteroate synthase
68
Q

Sulfonamides resistance

A

Plasmid transfers / random mutations that:
• Altered dihydropteroate synthase
• Decreased cellular permeability
• Enhanced PABA production
• Decreased intracellular drug accumulation

69
Q

Sulfonamides PK and SE

A
  • Oral or topical
  • Can accumulate in renal failure
  • Acetylated in liver. Can precipitate at neutral or acidic pH -> kidney damage

SE
• GI distress, fever, rashes, photosensitivity are common
• Crystalluria (nephrotoxicity)
• Hypersensitivity reactions
• Hematopoietic disturbances (esp. patients with G6PD deficiency)
• Kernicterus (in newborns and infants <2 months)

70
Q

Sulfonamides interactions and CI

A

• Warfarin, phenytoin and methotrexate can lead to increased plasma levels

SE
• Newborns & infants < 2 months (kernicterus) – drugs compete with bilirubin for binding sites on albumin

71
Q

Trimethoprim

A
  • Structurally similar to folic acid
  • Bacteriostatic against Gram-positive & Gram-negative organisms
  • UTI’s
  • Bacterial prostatitis
  • Bacterial vaginitis
  • Potent inhibitor of bacterial dihydrofolate reductase
  • Inhibits purine, pyrimidine & amino acid synthesis

PK
• Mostly (80-90%) excreted unchanged through kidney
• Reaches high concentrations in prostatic & vaginal fluids

SE
• Antifolate effects (contraindicated in pregnancy)
• Skin rash, pruritus

72
Q

Cotrimoxazole

A
  • Combination of trimethoprim & sulfamethoxazole
  • Bactericidal
  • Uncomplicated UTI’s (drug of choice) • PCP (drug of choice)
  • Nocardiosis (drug of choice)
  • Toxoplasmosis (alternative drug)
  • Respiratory, ear, sinus infections (H.influenzae, M.catarrhalis)

Mechanism of action
• Synergistic: inhibition of sequential steps in tetrahydrofolic acid synthesis

73
Q

Cotrimoxazole PK and SE

A
  • Oral admin. generally (can be given IV)
  • Well distributed (including CSF)
SE
• Dermatologic (common)
• GI
• Hematologic (hemolytic anemia)
• AIDS patients = higher incidence
• Contraindicated in pregnancy (esp. 1st trimester)
74
Q

Metronidazole

A

• Antimicrobial, amebicide & antiprotozoal
• Activity against anaerobic bacteria (including
bacteroides & Clostridium)
• Bactericidal

  • Anaerobic conditions are vital for optimal activity
  • Undergoes reductive bioactivation of its nitro group by ferredoxin
  • Forms cytotoxic products that interfere with nucleic acid synthesis
  • C.difficile infections (drug of choice)
  • Anaerobic or mixed intra-abdominal infections
  • Vaginitis (trichomonas & bacterial vaginosis, G.vaginalis) • Brain abscesses
  • H.pylori eradication (in combination)
75
Q

Metronidazole PK and SE

A
  • Oral, IV, rectal or topical
  • Wide distribution (including CSF)
  • Elimination = hepatic metabolism

SE
• GI irritation, stomatitis, peripheral neuropathy (prolonged use)
• Headache, dark coloration of urine
• Leukopenia, dizziness, ataxia (rarer)
• Opportunistic fungal infections
• Disulfiram-like effect (avoid alcohol)
• Use generally not advised in 1st trimester

76
Q

Nitrofurantoin

A
  • Urinary antiseptics. Oral agents with antibacterial activity in urine but little or no systemic effect
  • Use is limited to prophylaxis and treatment of lower UTI’s
  • Bacteriostatic & bactericidal
  • Active against many Gram-positive and Gram-negative bacteria
  • Reduction of nitrofurantoin by bacteria in the urine leads to formation of reactive intermediates that subsequently damage bacterial DNA
  • Slow emergence of resistance and no cross-resistance
77
Q

Nitrofurantoin PK, SE, CI

A

Pharmacokinetics
• Rapid elimination (only achieves adequate concentrations in urine)

Adverse Effects
• Anorexia, nausea & vomiting.
•Neuropathies, hemolytic anemia (G6PD deficient patients)

CI
• Significant renal insufficiency
• Pregnancy at term (38-42 weeks)
• Infants <1 month (risk of hemolytic anemia)

Term 5 Flash Cards (16 decks)

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