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.

*withdrawn from the market in 1999

Generation Drug Names Spectrum

1stnalidixic acid cinoxacin

Gram- but not Pseudomonas species

2nd

norfloxacinciprofloxacin enoxacin ofloxacin

Gram- (including Pseudomonas species), some Gram+ (S. aureus) and some atypicals

3rd

levofloxacin sparfloxacin moxifloxacingemifloxacin

Same as 2nd generation with extended Gram+ and atypical coverage

4th*trovafloxacin Same as 3rd generation

with broad anaerobic coverage

Mechanism of Action• Dual MOA:

1. Inhibition of bacterial DNA Gyrase (Topoisomerase II) 1. Formation of quinolone-DNA-Gyrase complex2. Induced cleavage of DNA

2. Inhibition of bacterial Topoisomerase IV1. Mechanism poorly understood

Mechanism of DNA Gyrase

Mechanism of Action

Quinolones

• [Conc] > serum: – 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/PDQuinolones PK/PD Bactericidal antibioticsBactericidal antibiotics Show both timeShow both time--dependent and a combination of timedependent and a combination of time--

dependent and concentration dependent killingdependent and concentration dependent killing

TimeTime--Dependent vs. ConcentrationDependent vs. Concentration--Dependent KillingDependent Killing

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

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 absorptionADRs– Blood glucose disturbances in DM patients– QTC prolongation, torsades de pointes, arrhythmias– Nausea, GI upset– Interstitial nephritis

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 <18 y.o.

• ADRs– 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*:– 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

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

• Tetracycline• Doxycycline*• Minocycline• Tigecycline

www.3dchem.com

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+]

www.3dchem.com

www.wikipedia.org

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://sitemaker.umich.edu/mc9/files/doxycycline.jpg

http://www2d.biglobe.ne.jp/~chem_env/chem8/doxycycline.gif

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

Doxycycline - Special Populations

• Pregnancy– Category D, but use in pregnancy andUse 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 5-14 days.

• FDA indications: complicated SSTIs and intraabdominal infections

http://www.rxlist.com/cgi/images/tygacil1.gif

http://www.wyeth.de/images/packshot_tygacil_thumb.jpg

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

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:– 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 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• 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.