Antibacterials 5 Flashcards
Name 2 Streptogramins?
Quinupristin, Dalfopristin
Describe Streptogramins and MOA?
• 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
Streptogramins Antibacterial Spectrum?
• Gram-positive cocci
• Multi-drug resistant bacteria (streptococci, PRSP(penicilin resistant S pneumoniae),
MRSA, E.faecium)
Streptogramins Clinical Applications?
• Restricted to treatment of infections caused by drug resistant Staphylococci or VRE
Streptogramins PK?
- IV only
- Penetrates macrophages & polymorphonucleocytes
- Inhibitors of CYP 3A4
Streptogramins AE?
- Infusion related (venous irritation, arthralgia & myalgia)
- GI effects
- CNS effects (headache, pain)
Linezolid MOA and Describe?
• 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
Linezeolid Resistance?
- Decreased binding to target site
- Point mutation of ribosomal RNA
- No cross-resistance with other drug classes
Linezolid Antibacterial Spectrum?
• Most Gram-positive organisms (staphylococci,
streptococci, enterococci, Corynebacterium, Listeria
monocytogenes) including MRSA and VRE
• Moderate activity against mycobacterium tuberculosis
Linezolid Clinical Applications and PK?
• Treatment of multi-drug resistant infections PK: • Oral (100% bioavailable) & IV • Widely distributed (including CSF) • Weak reversible inhibitor of MAO
Linezolid AE and Contraindications?
• 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
Describe Fidaxomicin activity and spectrum?
• Narrow spectrum macrocyclic antibiotic
• Activity against Gram-positive aerobes and
anaerobes especially Clostridia
• No activity against Gram-negative bacteria
Fidaxomicin MOA??
PK?
• Inhibits bacterial protein synthesis by binding to RNA
polymerase
PK:
• When administered orally, systemic absorption is
negligible but fecal concentrations are high
Fidaxomicin AE?
- Main effects appear to be gastrointestinal disorders
* The safety and effectiveness of fidaxomicin in patients < 18 years of age have not been established.
Describe Mupirocin?
• 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
Mupirocin MOA and AE?
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)
Mupirocin Clinical Applications?
• Intranasal:
• Eradication of nasal colonization with MRSA in
adult patients and healthcare workers
• Topically:
• Treatment of impetigo or secondary infected
traumatic skin lesions
Which 3 drugs affects nucleic acid synthesis?
- Fluoroquinolones
- Sulfonamides
- Trimethoprim
List the Fluoroquinolones by generation?
First generation- Nalidixic Acid (quinolone) Second generation- Ciprofloxacin Third generation- Levofloxacin Fourth generation- Gemifloxacin, Moxifloxacin
Fluoroquinolones MOA?
- Broad spectrum, bactericidal drugs
- Enter bacterium via porins
- Inhibit bacterial DNA replication via interference with topoisomerase II (DNA gyrase) & IV
Fluoroquinolones Resistance?
- 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
Describe antibacterial spectrum of fluoroquinolones?
- Classified into generations
- Lower generations have excellent Gram-negative activity
- Higher generations have improved activity against Grampositives
Antimicrobial spectrum of 1st and 2nd generation fluoroquinolone?
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
Antimicrobial spectrum of 3rd and 4th generation fluoroquinolone?
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
Clinical Applications of 3rd and 4th generation fluoroquinolone?
3rd Levofloxacin Prostatitis STD’s (not syphilis) Skin infections Acute sinusitis, bronchitis, TB Community acquired pneumonia
4th Moxifloxacin,
Gemifloxacin
Community acquired pneumonia
Clinical Applications of 1st and 2nd generation fluoroquinolone?
1st Nalidixic acid Uncomplicated UTI’s
2nd Ciprofloxacin Travelers diarrhea
P.aeruginosa (CF patients)
Prophylaxis against meningitis
(alternative to ceftriaxone & rifampin)
Describe Respiratory Fluoroquinolones?
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
Fluoroquinolones PK?
• 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)
Fluoroquinolones AE?
• 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)
Contraindications and Interactions with Fluoroquinolones?
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)
Name the 3 Sulfonamides?
Sulfamethoxazole, Sulfadiazine, Sulfasalazine
Describe Sulfonamides?
• Structural analogs of p-aminobenzoic acid (PABA)
• Bacteriostatic against Gram-positive & Gram-negative
organisms
Sulfonamides MOA?
• Inhibit bacterial folic acid synthesis
• Synthetic analogs of PABA (p-amino-benzoic acid)
• Competitive inhibitors (& substrate) of dihydropteroate
synthase
Sulfonamide resistance?
Plasmid transfers / random mutations that:
• Altered dihydropteroate synthase
• Decreased cellular permeability
• Enhanced PABA production
• Decreased intracellular drug accumulation
Sulfonamide Clinical Applications?
Infrequently used as single agents (resistance)
• Topical agents (ocular, burn infections)
• Oral agents (simple UTI’s)
• Sulfasalazine (oral) = ulcerative colitis, enteritis, IBD
Sulfonamide PK?
• Oral or topical
• Can accumulate in renal failure
• Acetylated in liver. Can precipitate at neutral or acidic pH
-> kidney damage
Sulfonamide AE?
• 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)
Sulfonamide Drug Interactions? Contraindication?
• 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
Describe Trimethoprim and MOA?
• 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
Trimethoprim Clinical Applications?
- UTI’s
- Bacterial prostatitis
- Bacterial vaginitis
Trimethoprim PK?
- Mostly (80-90%) excreted unchanged through kidney
* Reaches high concentrations in prostatic & vaginal fluids
Trimethoprim AE?
- Antifolate effects (contraindicated in pregnancy)
* Skin rash, pruritus
