Transcript Quinolones, Metronidazole, Tetracyclines, Trimethoprim

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
Quinolones
• Parent drug: nalidixic acid
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.
Generation
Drug Names
Spectrum
1st
nalidixic acid
cinoxacin
Gram- but not
Pseudomonas species
2nd
norfloxacin
ciprofloxacin
enoxacin
ofloxacin
Gram- (including
Pseudomonas species),
some Gram+ (S. aureus)
and some atypicals
3rd
levofloxacin
sparfloxacin
moxifloxacin
gemifloxacin
Same as 2nd generation
with extended Gram+ and
atypical coverage
*trovafloxacin
Same as 3rd generation
with broad anaerobic
coverage
4th
*withdrawn from the market in
1999
Mechanism of Action
•
Dual MOA:
1.
Inhibition of bacterial DNA Gyrase (Topoisomerase II)
1.
2.
2.
Formation of quinolone-DNA-Gyrase complex
Induced cleavage of DNA
Inhibition of bacterial Topoisomerase IV
1.
Mechanism poorly understood
Mechanism of DNA Gyrase
Mechanism of Action
Quinolones
• [Conc] > serum:
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Prostate tissue
Stool
Bile
Lung
Neutrophils
Macrophages
Kidneys
• [Conc] < serum:
– Prostatic tissue fluid
– Bone
– CSF
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)
Quinolones PK/PD


Bactericidal antibiotics
Show both time-dependent and a combination of timedependent and concentration dependent killing
Time-Dependent vs. Concentration-Dependent Killing
Ciprofloxacin
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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
Levofloxacin
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•
•
•
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:
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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
Moxifloxacin
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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:
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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 <18 y.o.
•
ADRs
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Blood glucose disturbances in DM patients
QTC prolongation, torsades de pointes, arrhythmias
Nausea, GI upset
Interstitial nephritis
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-)
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
Metronidazole
• Indications*:
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Anaerobe infections
C. difficile
H. pylori
Bacterial vaginosis
Trichomonas vaginitis
Amebiasis
Giardiasis
* Dose can vary by indication
• Drug interactions:
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EtOH
Antacids
CyA/tacrolimus
Lithium
Phenytoin
Rifampin
Warfarin
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
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
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•
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Tetracycline
Doxycycline*
Minocycline
Tigecycline
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Mechanism of Action
• Passive diffusion
www.solvo.com
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
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+]
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m
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
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: <10 mL/min: every 24 hours
• Hepatic insufficiency
– Avoid use
– If necessary, maximum 1g/day
Doxycycline
• Dosing:
– Adults: 100-200 mg/day
in 1-2 divided doses PO
or IV
– Peds: > 45 kg use adult
dosing
• < 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/doxycycline.gif
http://sitemaker.umich.edu/mc9/files/doxycycline.jpg
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
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Discoloration of teeth
Diarrhea
Rash
Photosensitivity
Urticaria
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
Tigecycline
• Dosing:
– Adults: initial dose of
100 mg. Maintenance
dose: 50 mg q12h x 514 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
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:
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N/V/D
Hypertension
Edema
Hypotension
Headache
Rash
Pruritus
Local irritation
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
Tigecycline
• Aerobic and
facultative gram
negative organisms:
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–
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Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Klebsiella species
• Anaerobic organisms:
– Bacteroides species
(including fragilis)
– Clostridium
perfringens
– Peptostreptococcus
micros
Tigecycline
• Distribution:
– [Gall bladder], [Colon], [Lung] > [Serum]
– [Bone], [Synovial fluid] < [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%)
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 paraaminobenzoic 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
• SMX:TMP is a 5:1 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.
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.
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.
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 > 2.6: 160 mg q 36 h
– Hemodialysis: Load with 160 mg, then 80 mg
after each dialysis.