Fluoroquinolones

Question 1

fluoroquinolones are derivates of

Answer 1

nalidixic acid

Question 2

when fluoroquinolones were developed their main benefits were

Answer 2

Broad spectrum of activity

Improved PK properties – excellent oral bioavailability, tissue penetration, long half-lives

Question 3

fluoroquinolones mechanism of action

Answer 3

Inhibit DNA synthesis by inhibiting bacterial topoisomerases necessary for DNA synthesis

FQs display rapid, concentration-dependent bactericidal activity

Question 4

primary target of fluoroquinolones in gram (-) bacteria

Answer 4

DNA gyrase (topoisomerase II) – removes excess positive supercoiling in the DNA helix

• FQs form stable complex with DNA and DNA gyrase, which blocks DNA replication
• Primary target in gram-negative bacteria

Question 5

primary target of fluoroquinolones in gram (+) bacteria

Answer 5

Topoisomerase IV – essential for separation of interlinked daughter DNA molecules

• FQs interfere with separation of daughter cells
• Primary target for many gram-positive bacteria

Question 6

Mechanisms of Resistance of fluoroquinolones

Answer 6

• Altered target sites – chromosomal mutations in genes that code for DNA gyrase or topoisomerase IV lead to decreased binding affinity
-Most important and most common
• Expression of active efflux – transfers FQs out of cell
• Altered cell wall permeability – decreased porin expression
• Plasmid mediated resistance
• Cross-resistance occurs between FQs (if resistant to one it will be resistant to them all)

Question 7

The Available FQs

Answer 7

older:
Ciprofloxacin (Cipro®) – PO, IV

newer:
Levofloxacin (Levaquin®) – PO, IV
Moxifloxacin (Avelox®) – PO, IV

Question 8

which FQs have the best gram positive aerobe activity

Answer 8

Moxifloxacin and levofloxacin

Question 9

target organism for newer FQs

Answer 9

Streptococcus pneumoniae (including PRSP)*

Question 10

which FQs have activity against Pseudomonas?

Answer 10

ciprofloxacin and levofloxacin with best activity but significant resistance has evolved (originally was the target organism)

NOT moxi

Question 11

which FQs have the best activity against Enterbacteriaceae and H. influenzae

Answer 11

cipro and levo (best gram - aerobe activity)

Question 12

which FQ is best for anaerobes

Answer 12

Moxifloxacin (but more and more resistance is developing)

Question 13

which FQs have the best activity against atypically bacteria such as

Legionella pneumophila – DOC*
Chlamydophila and Chlamydia spp.
Mycoplasma spp.
Ureaplasma urealyticum

Answer 13

All have good activity

Question 14

FQ absorption

Answer 14

very good bioavailability when given orally

Question 15

FQ distribution

Answer 15

Extensive tissue distribution – lung; skin/soft tissue and bone; urinary tract and prostate (cipro, levo)

Moxi has good CSF penetration

Question 16

FQ elimination

Answer 16

Renally eliminated: levofloxacin (90%), ciprofloxacin (60%), gemifloxacin (36%)
Dosage adjustment required in the presence of renal insufficiency

Hepatically eliminated: moxifloxacin (80%)

Question 17

Fluoroquinolones most common clinical use

Answer 17

respiratory tract infections

Upper Respiratory Tract Infections
Sinusitis, bronchitis– levo, moxi, gemi, cipro

Lower Respiratory Tract Infections
• Community-acquired pneumonia - levo, moxi, gemi (Not cipro due to poor gram + coverage)
• Nosocomial (hospital acquired) pneumonia – anti-pseudomonal FQ’s: cipro (in combination with Gram + agent) & levo
• Exacerbations in cystic fibrosis - cipro

Question 18

clinical uses for FQs

Answer 18

• Respiratory tract infections
• Urinary tract infections pyelonephritis, prostatitis – cipro, levo
• Other: bone, intraabdominal (with metronidazole), STDs, TB (levo, moxi)

Question 19

Fluoroquinolones
 Adverse Effects

Answer 19

MANY - At least 7 FQs have been removed from the market due to adverse effects

Most common are GI and CNS
Prolongation on QTc interval
Tendonitis, tendon rupture
Hepatotoxicity, photosensitivity, hypersensitivity, rash, articular damage

Question 20

cardiac adverse effects for FQs

Answer 20

• Prolongation of QTc interval – may lead to Torsades
• Use with caution in patients with hypokalemia, preexisting QT prolongation, concomitant antiarrhythmics
• Use caution in combination with other drugs that prolong the QT (effects can be additive)

get a baseline Ekg before starting

Question 21

which patient populations are FQs contraindicated for

Answer 21

contraindication in pediatric patients and pregnant or breastfeeding women due to the articular cartilage damage

Question 22

important drug interactions with FQs

Answer 22

• Divalent and trivalent cations – ALL PO FQs
Zinc, Iron, Calcium, Aluminum, Magnesium
Antacids, sucralfate, didanosine, enteral feedings, calcium-rich foods (orange juice)
Impair absorption of orally-administered FQs – may lead to CLINICAL FAILURE
Administer doses 2 to 4 hours apart; administer the FQ first
• Warfarin – idiosyncratic, all FQs
• Theophylline and Cyclosporine - cipro
Inhibition of metabolism → ↑ levels, ↑ toxicity

Question 23

best FQs for community acquired pneumonia

Answer 23

levo, moxi, gemi

Question 24

best FQs for healthcare associate pneumonia

Answer 24

cipro (w/ another antibiotic for gram + coverage), levo

HCAP needs to cover pseudomas

Question 25

which FQs are good for Sinusitis, bronchitis

Answer 25

all

Question 26

which FQs are good for UTI, prostatitis

Answer 26

cipro, levo

Question 27

what is Metronidazole active against

Answer 27

protozoa and anaerobes

Question 28

what is metronidazones mechanism of action

Answer 28

given as a prodrug that ultimatly becomes activated and inhibits DNA synthesis of the bacteria Metronidazole displays concentration-dependent bactericidal activity

Question 29

mechanisms of resistance for metronixazone

Answer 29

both are fairly uncommon 1. Altered growth requirements – organisms grows in higher local oxygen concentrations causing decreased activation of metronidazole 2. Altered ferredoxin levels – reduced transcription of the ferredoxin gene; less activation of metronidazole

Question 30

target organisms for metronidazones

Answer 30

bacteroides ssp. and clostridium spp

Question 31

metronidazone absorption

Answer 31

available IV and PO | Rapidly and completely absorbed (F > 90%); food with minimal effect on absorption

Question 32

metronidazone distribution

Answer 32

Good serum concentrations with PO or IV | Well absorbed into body tissues and fluids; **DOES penetrate the CSF

Question 33

metronidazone elimination

Answer 33

Metronidazole is primarily metabolized by the liver (metabolites excreted in urine); 6 to 15% excreted in the feces; half-life is 6 to 8 hours Metronidazole is removed during hemodialysis

Question 34

clinical uses of metronidazone

Answer 34

``` Anaerobic Infections (including in the CNS) Intraabdominal, pelvic, skin/soft tissue, diabetic foot and decubitus ulcer infections; brain abscess ``` Pseudomembranous colitis due to C. difficile Metronidazole is the drug of Choice for MILD to MODERATE c.dif disease PO or IV Other Bacterial vaginosis, Trichomonas, Amebiasis, H. pylori, Rosacea, Gingivitis

Question 35

adverse reactions to metronidazone

Answer 35

• Gastrointestinal- Most common ADR Nausea, vomiting, stomatitis, metallic taste • CNS – most serious Peripheral neuropathy*, seizures, encephalopathy Use with caution in patients with preexisting CNS disorders Requires discontinuation of metronidazole • Mutagenicity, carcinogenicity Avoid during pregnancy and breastfeeding*

Question 36

metronidazone drug interactions

Answer 36

warfarin- ↑ Anticoagulant effect | alcohol - sever nausea and flushing (Disulfiram reaction)