Quinolones

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Quinolones

• Drugs norfloxacin, ciprofloxacin, ofloxacin,
  levofloxacin, moxifloxacin
• Mechanism of action
• Inhibit bacterial DNA synthesis by inhibiting DNA
  gyrase and topoisomerase IV ? rapid cell death
• Post antibiotic effect lasts 1 to 2 hours,
  increases with increasing concentration
• Mechanism of resistance
• Chromosomal
• Alter target enzymes DNA gyrase and
  topoisomerase IV
• Decreased drug penetration Pseudomonas, E. coli
• Plasmid seen in some K. pneumoniae and E. coli
• Mutations in both target enzymes are needed to
  produce significant resistance

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Quinolones

• Parent drug nalidixic acid

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Classification

• Quinolones (1st generation)
• Highly protein bound
• Mostly used in UTIs
• Fluoroquinolones (2nd, 3rd and 4th generation)
• Modified 1st generation quinolones
• Not highly protein bound
• Wide distribution to urine and other tissues
  limited CSF penetration.

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Mechanism of Action

• Dual MOA
• Inhibition of bacterial DNA Gyrase (Topoisomerase
  II)
• Formation of quinolone-DNA-Gyrase complex
• Induced cleavage of DNA
• Inhibition of bacterial Topoisomerase IV
• Mechanism poorly understood
• Mechanism of DNA Gyrase

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Mechanism of Action
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Quinolones

• Conc gt serum
• Prostate tissue
• Stool
• Bile
• Lung
• Neutrophils
• Macrophages
• Kidneys

• Conc lt serum
• Prostatic tissue fluid
• Bone
• CSF

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Quinolones

• Drug interactions
• ? absorption Al3, Mg2, and Ca2 antacids
• CYP450 inhibition potential drug interactions for
  ciprofloxacin
• (Ex) can increase warfarin exposure (real changes
  in INR are rare, but monitor)
• Adverse effects
• GI Nausea, vomiting
• CNS HA, dizziness, confusion, insomnia,
  delerium, hallucinations, seizure (rare)
• Cardiovascular Torsades de pointes (rare)
• Musculoskeletal Rupture of tendon (rare)
• Neurologic Polyneuropathy (rare)

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Quinolones PK/PD

• Bactericidal antibiotics
• Show both time-dependent and a combination of
  time-dependent and concentration dependent
  killing
• Time-Dependent vs.
  Concentration-Dependent Killing

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Ciprofloxacin

• Administration Usual Dosage IV, PO 500 750
  mg q 8-12h
• Spectrum Gram- aerobic rods, and Legionella
  pneumophila, and other atypicals. Poor activity
  against Strep. pneumoniae.
• Indications
• -- Nosocomial pneumonia
• -- Intra-abdominal infections
• Uncomplicated/complicated UTI
• Anthrax exposure and prophylaxis
• Unique Qualities
• Binds divalent cations (i.e. Ca Mg) which
  decreases absorption
• -- Increased effects of warfarin
• ADRs
• QTC prolongation, torsades de pointes,
  arrhythmias
• Nausea, GI upset
• Interstitial nephritis

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Levofloxacin

• Brand Name Levaquin, Quixin
• Administration Usual Dosage IV, PO and
  ophthalmic 500-750 mg q24h
• Spectrum Gram-, Gram (S. aureus including MRSA
  S. pneumoniae) and Legionella pneumophila,
  atypical resp. pathogens,
• Mycobacterium tuberculosis
• Indications
• Chronic bronchitis and CAP
• -- Nosocomial pneumonia
• SSTIs
• Intra-abdominal infections
• Unique Qualities
• Binds divalent cations (i.e. Ca Mg) which
  decreases absorption
• ADRs
• Blood glucose disturbances in DM patients
• QTC prolongation, torsades de pointes,
  arrhythmias
• Nausea, GI upset
• Interstitial nephritis

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Moxifloxacin

• Brand Name Avelox, Vigamox
• Administration Usual Dosage IV, PO and
  ophthalmic 400mg q24h
• Spectrum Gram-, Gram (S. aureus including MRSA
  S. pneumoniae) atypicals (L. pneumophila, C
  pneumonia M. pneumoniae), Mycobacterium
  tuberculosis, gram-negative anaerobes
• Indications
• Chronic bronchitis
• CAP
• Bacterial conjuctivitis
• Sinusitis
• Unique Qualities
• Binds divalent cations (i.e. Ca Mg) which
  decreases absorption
• Safety and efficacy not established in patients
  lt18 y.o.
• ADRs
• Blood glucose disturbances in DM patients
• QTC prolongation, torsades de pointes,
  arrhythmias
• Nausea, GI upset
• Interstitial nephritis

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Resistance Mechanisms

• Mutations that enhance antibiotic efflux
  capability
• Bacterial chromosomal mutations for genes that
  encode for bacterial DNA gyrase and Topo IV
• Mutations in outer membrane porins (Gram-)

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Metronidazole

• Mechanism of action
• Enters bacteria via cell diffusion
• Activated via single reduction step by bacteria?
  forms radicals ? reacts with nucleic acid ? cell
  death
• Spectrum of activity
• Anaerobic bacteria
• Microaerophilic bacteria
• Protozoa
• Resistance
• Rare
• Mechanism decreased activation (? redox
  reaction) of drug

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Metronidazole

• Indications
• Anaerobe infections
• C. difficile
• H. pylori
• Bacterial vaginosis
• Trichomonas vaginitis
• Amebiasis
• Giardiasis

• Drug interactions
• EtOH
• Antacids
• CyA/tacrolimus
• Lithium
• Phenytoin
• Rifampin
• Warfarin

Dose can vary by indication
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Metronidazole

• Distribution into tissue
• Therapeutic levels
• PMNs
• Unobstructed biliary tract
• Pancreas
• CSF
• Empyema fluid
• Peritoneal fluid
• Hepatic abscess
• Pelvic tissues
• Vaginal/seminal fluid

• Adverse Effects
• GI N, V, epigastric distress
• Metallic taste
• Darkening of urine
• Peripheral neuropathy
• Pancreatitis
• Hepatitis
• Fever
• Reversible neutropenia

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Tetracyclines

• Broad-spectrum activity
• Includes aerobic G and G-, atypicals Rickettsia
  spp, treponema spp, chlamydia spp, and others
• Little to no effect on fungi or viruses
• Tetracycline
• Doxycycline
• Minocycline
• Tigecycline

www.3dchem.com
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Mechanism of Action

• Passive diffusion

www.solvo.com
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Mechanism of Action

• Once inside the cell
• Bind 30S ribosomal subunit
• Blocks binding of aminoacyl-tRNA to acceptor site
  on mRNA-ribosome complex
• Protein synthesis is inhibited bacteriostatic
  effect

http//genomebiology.com/content/figures/gb-2003-4
-12-237-1.jpg
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Tetracycline

• Dosing
• Adult 250 - 500 mg PO q6h
• Peds 25 - 50 mg/kg/d q6h
• Food and milk decrease absorption about 50
• Administer at least 1-2 hours prior to or 4 hours
  after antacid or vitamins due to chelation Al3,
  Mg2, Ca2, Fe2

www.wikipedia.org
www.3dchem.com
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Tetracycline

• Dosage forms
• Capsule 250, 500 mg
• Tablet 250, 500 mg
• Suspension 125 mg/5 mL

• Adverse Effects
• Photosensitivity
• Discoloration of teeth
• N/V/D
• Candidal superinfection
• Hepatotoxicity

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Tetracycline - Special Populations

• Pregnancy
• Category D
• Enters breast milk
• Renal insufficiency
• CrCl 50-80 mL/min every 8-12 hours
• CrCl 10-50 mL/min every 12-24 hours
• CrCl lt10 mL/min every 24 hours
• Hepatic insufficiency
• Avoid use
• If necessary, maximum 1g/day

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Doxycycline

• Dosing
• Adults 100-200 mg/day in 1-2 divided doses PO or
  IV
• Peds gt 45 kg use adult dosing
• lt 45 kg 2-5 mg/kg/day in 1-2 divided doses.
  Max. 200 mg/day
• Give with meals to decrease GI upset
• Take with water and sit up for 30 minutes to
  avoid esophageal irritation

http//www2d.biglobe.ne.jp/chem_env/chem8/doxycyc
line.gif
http//sitemaker.umich.edu/mc9/files/doxycycline.j
pg
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Doxycycline

• Dosage forms
• Capsules
• Hyclate, monohydrate 50, 100 mg
• Coated pellets 75,100 mg
• Variable release 40mg - 30 immediate and 10
  delayed
• Injection 100 mg
• Suspension 25mg/5mL
• Tablet
• Hyclate 100 mg
• Monohydrate 50,75,100 mg
• Delayed-release coated pellets 75,100 mg

• Adverse Effects
• Discoloration of teeth
• Diarrhea
• Rash
• Photosensitivity
• Urticaria

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Doxycycline - Special Populations

• Pregnancy
• Category D, but use in pregnancy and
• Use in children single 5-7 day course for RMSF
  is safe
• Renal Insufficiency
• No adjustment necessary

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Tigecycline

• Dosing
• Adults initial dose of 100 mg. Maintenance dose
  50 mg q12h x 5-14 days.
• FDA indications complicated SSTIs and
  intraabdominal infections

http//www.wyeth.de/images/packshot_tygacil_thumb.
jpg
http//www.rxlist.com/cgi/images/tygacil1.gif
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Tigecycline

• Dosage forms
• Injection 50 mg
• Administration
• Infuse over 30-60 mins through dedicated line or
  via Y-site.
• Stable in D5W or NS

• Adverse Effects
• N/V/D
• Hypertension
• Edema
• Hypotension
• Headache
• Rash
• Pruritus
• Local irritation

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Tigecycline - Special Populations

• Pregnancy
• Category D
• Not recommended - crosses placenta
• Renal Insufficiency
• No dosage adjustment required
• Hepatic Impairment
• Severe initial dose 100 mg followed by 25 mg q12h

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Tigecycline

• Aerobic and facultative gram negative organisms
• Citrobacter freundii
• Enterobacter cloacae
• Escherichia coli
• Klebsiella species

• Anaerobic organisms
• Bacteroides species (including fragilis)
• Clostridium perfringens
• Peptostreptococcus micros

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Tigecycline

• Distribution
• Gall bladder, Colon, Lung gt Serum
• Bone, Synovial fluid lt Serum
• Elimination
• Mostly feces/biliary excretion (59)
• Some excretion in urine (33)
• Adverse Effects (incidence)
• Nausea (29.5)
• Vomiting (19.7)
• Diarrhea (12.7)
• Local reaction (9.0)

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TMP/SMX

• Good activity against Gr () and Gr (-)
  organisms MRSA, very active against PCP.
  Covers Stenotrophomonas maltophila, Nocardia, and
  enteric gram-negative rods.
• Exceptions Pseudomonas aeruginosa, Group A
  strep, enterococcus, Gr (-) anaerobes.
• MOA Sulfamethoxazole interferes with bacterial
  folic acid synthesis and growth via inhibition of
  dihydrofolic acid formation from
  para-aminobenzoic acid trimethoprim blocks the
  production of tetrahydrofolic acid by inhibiting
  the enzyme dihydrofolate reductase.
• Use with caution in pts with severe G6PD
  deficiency
• Toxicity GI upset, rash can progress to SJS and
  TEN, thrombocytopenia, leucopenia, hepatitis
  hyperkalemia
• SMXTMP is a 51 ratio, in oral and IV dosage
  forms.
• 10-20 mg/kg (of TMP) daily, in 2 to 4 divided
  doses (q 6 h) for PCP, Nocardia,
  Stenotrophomonas, GNR DS 2 BID for MRSA.

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Colistin (polymyxin E)

• MOA binds to lipopolysaccharide on outer cell
  wall of GNR permeability change in cell
  envelope leakage of cell content.
• Formulation, IV colistimethate hydrolyzed to
  colistin.
• PK/PD negligible oral absorption, predominant
  renal elimination concentration-dependent
  activity.

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Colistin

• Spectrum aerobic gram-negative rods, including
  Acinetobacter, Ps. aeruginosa, Stenotrophomonas.
• NOT active against Burkholdaria, Proteus,
  Serratia, Brucella, gram-negative anaerobes,
  gram-positive cocci
• Adverse effects ATN Neurotoxicity dizziness,
  weakness, vertigo, visual changes, confusion,
  ataxia.

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Colistin

• Dosing regimens (poorly defined)
• 2.5 to 5 mg/kg/day in 2-4 doses
• For SCr 1.3 1.5 160 mg q 12h
• SCr 1.6 2.5 160 mg q 24 h
• SCr gt 2.6 160 mg q 36 h
• Hemodialysis Load with 160 mg, then 80 mg after
  each dialysis.