Antibacterials 5

Question 1

Name 2 Streptogramins?

Answer 1

Quinupristin, Dalfopristin

Question 2

Describe Streptogramins and MOA?

Answer 2

• Given as a combination (act synergistically to have
bactericidal action)
• Long postantibiotic effect
Mechanism of action
• Bind to separate sites on 50S bacterial ribosome
• Resistance is uncommon

Question 3

Streptogramins Antibacterial Spectrum?

Answer 3

• Gram-positive cocci
• Multi-drug resistant bacteria (streptococci, PRSP(penicilin resistant S pneumoniae),
MRSA, E.faecium)

Question 4

Streptogramins Clinical Applications?

Answer 4

• Restricted to treatment of infections caused by drug resistant Staphylococci or VRE

Question 5

Streptogramins PK?

Answer 5

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

Question 6

Streptogramins AE?

Answer 6

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

Question 7

Linezolid MOA and Describe?

Answer 7

• Bacteriostatic (cidal against streptococci & Clostridium
perfringens)
Mechanism of action
• Inhibits formation of 70S initiation complex
• Binds to unique site on 23S ribosomal RNA of 50S
subunit

Question 8

Linezeolid Resistance?

Answer 8

• Decreased binding to target site
• Point mutation of ribosomal RNA
• No cross-resistance with other drug classes

Question 9

Linezolid Antibacterial Spectrum?

Answer 9

• Most Gram-positive organisms (staphylococci,
streptococci, enterococci, Corynebacterium, Listeria
monocytogenes) including MRSA and VRE
• Moderate activity against mycobacterium tuberculosis

Question 10

Linezolid Clinical Applications and PK?

Answer 10

• Treatment of multi-drug resistant infections
PK:
• Oral (100% bioavailable) & IV
• Widely distributed (including CSF)
• Weak reversible inhibitor of MAO

Question 11

Linezolid AE and Contraindications?

Answer 11

• Well tolerated for short admin. (GI, nausea, diarrhea,
headaches, rash)
Long-term admin. can cause:
• Bone marrow suppression, esp. thrombocytopenia
• Optic & peripheral neuropathy, & lactic acidosis
• Serotonin syndrome

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

Question 12

Describe Fidaxomicin activity and spectrum?

Answer 12

• Narrow spectrum macrocyclic antibiotic
• Activity against Gram-positive aerobes and
anaerobes especially Clostridia
• No activity against Gram-negative bacteria

Question 13

Fidaxomicin MOA??

PK?

Answer 13

• Inhibits bacterial protein synthesis by binding to RNA
polymerase
PK:
• When administered orally, systemic absorption is
negligible but fecal concentrations are high

Question 14

Fidaxomicin AE?

Answer 14

• Main effects appear to be gastrointestinal disorders

* The safety and effectiveness of fidaxomicin in patients < 18 years of age have not been established.

Question 15

Describe Mupirocin?

Answer 15

• 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

Question 16

Mupirocin MOA and AE?

Answer 16

MOA:
• Binds to bacterial isoleucyl transfer-RNA synthetase
resulting in the inhibition of protein synthesis
AE:
• Resistance develops if used for long periods of time
• Mainly local and dermatologic effects (eg, burning,
edema, tenderness, dry skin, pruritus)

Question 17

Mupirocin Clinical Applications?

Answer 17

• Intranasal:
• Eradication of nasal colonization with MRSA in
adult patients and healthcare workers
• Topically:
• Treatment of impetigo or secondary infected
traumatic skin lesions

Question 18

Which 3 drugs affects nucleic acid synthesis?

Answer 18

• Fluoroquinolones
• Sulfonamides
• Trimethoprim

Question 19

List the Fluoroquinolones by generation?

Answer 19

First generation-
Nalidixic Acid (quinolone)
Second generation-
Ciprofloxacin
Third generation-
Levofloxacin
Fourth generation-
Gemifloxacin, Moxifloxacin

Question 20

Fluoroquinolones MOA?

Answer 20

• Broad spectrum, bactericidal drugs
• Enter bacterium via porins
• Inhibit bacterial DNA replication via interference with topoisomerase II (DNA gyrase) & IV

Question 21

Fluoroquinolones Resistance?

Answer 21

• Emerged rapidly in 2nd generation
• Due to chromosomal mutations that:
• encode subunits of DNA gyrase and topo IV
• regulate expression of efflux pumps
• Cross-resistance between drugs occurs

Question 22

Describe antibacterial spectrum of fluoroquinolones?

Answer 22

• Classified into generations
• Lower generations have excellent Gram-negative activity
• Higher generations have improved activity against Grampositives

Question 23

Antimicrobial spectrum of 1st and 2nd generation fluoroquinolone?

Answer 23

1st Nalidixic acid Moderate Gram -ve activity

2nd Ciprofloxacin Expanded Gram -ve activity
Some activity against Gram +ve and atypical organisms.
Synergistic with
beta-lactams

Question 24

Antimicrobial spectrum of 3rd and 4th generation fluoroquinolone?

Answer 24

3rd Levofloxacin Expanded Gram -ve activity
Improved activity against Gram +ve and atypical organisms.
Excellent activity against
S.pneumoniae

4th Moxifloxacin,
Gemifloxacin
Improved Gram +ve activity and
anaerobic activity

Question 25

Clinical Applications of 3rd and 4th generation fluoroquinolone?

Answer 25

``` 3rd Levofloxacin Prostatitis STD’s (not syphilis) Skin infections Acute sinusitis, bronchitis, TB Community acquired pneumonia ``` 4th Moxifloxacin, Gemifloxacin Community acquired pneumonia

Question 26

Clinical Applications of 1st and 2nd generation fluoroquinolone?

Answer 26

1st Nalidixic acid Uncomplicated UTI’s 2nd Ciprofloxacin Travelers diarrhea P.aeruginosa (CF patients) Prophylaxis against meningitis (alternative to ceftriaxone & rifampin)

Question 27

Describe Respiratory Fluoroquinolones?

Answer 27

Levofloxacin, moxifloxacin & gemifloxacin (excellent activity against most common causes of pneumonia) Used in treatment of pneumonia when: • First-line agents have failed • In the presence of comorbidities • Patient is an inpatient

Question 28

Fluoroquinolones PK?

Answer 28

• 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)

Question 29

Fluoroquinolones AE?

Answer 29

• GI distress • CNS, rash, photosensitivity • Connective tissue problems (avoid in pregnancy, nursing mother, under 18’s) – Black Box Warning! • Peripheral neuropathy (FDA warning) • QT prolongation (moxifloxacin, gemifloxacin, levofloxacin) • High risk of causing superinfections (C.difficile, C albicans, streptococci)

Question 30

Contraindications and Interactions with Fluoroquinolones?

Answer 30

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

Question 31

Name the 3 Sulfonamides?

Answer 31

Sulfamethoxazole, Sulfadiazine, Sulfasalazine

Question 32

Describe Sulfonamides?

Answer 32

• Structural analogs of p-aminobenzoic acid (PABA) • Bacteriostatic against Gram-positive & Gram-negative organisms

Question 33

Sulfonamides MOA?

Answer 33

• Inhibit bacterial folic acid synthesis • Synthetic analogs of PABA (p-amino-benzoic acid) • Competitive inhibitors (& substrate) of dihydropteroate synthase

Question 34

Sulfonamide resistance?

Answer 34

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

Question 35

Sulfonamide Clinical Applications?

Answer 35

Infrequently used as single agents (resistance) • Topical agents (ocular, burn infections) • Oral agents (simple UTI’s) • Sulfasalazine (oral) = ulcerative colitis, enteritis, IBD

Question 36

Sulfonamide PK?

Answer 36

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

Question 37

Sulfonamide AE?

Answer 37

• 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)

Question 38

Sulfonamide Drug Interactions? Contraindication?

Answer 38

• Can displace other drugs from albumin eg, warfarin, phenytoin and methotrexate • Newborns & infants < 2 months (kernicterus) – drugs compete with bilirubin for binding sites on albumin

Question 39

Describe Trimethoprim and MOA?

Answer 39

• Structurally similar to folic acid • Bacteriostatic against Gram-positive & Gram-negative organisms MOA: • Potent inhibitor of bacterial dihydrofolate reductase • Inhibits purine, pyrimidine & amino acid synthesis

Question 40

Trimethoprim Clinical Applications?

Answer 40

* UTI’s * Bacterial prostatitis * Bacterial vaginitis

Question 41

Trimethoprim PK?

Answer 41

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

Question 42

Trimethoprim AE?

Answer 42

* Antifolate effects (contraindicated in pregnancy) | * Skin rash, pruritus