Fluoroquinolones & Metronidazole

Question 1

Fluoroquinolones

Answer 1

Developed in response to growing resistance.
Are FLUORINATED quinolones, hence the name.
Examples:
Ciprofloxacin
Levofloxacin
Moxifloxacin
Gemifloxacin

Question 2

Fluoroquinolones Mech of Action

Answer 2

INHIBITION OF DNA SYNTHESIS by binding to/inhibiting topoisomerases.

FQs target DNA GYRASE (aka topoisomerase type II, required to undue supercoiling during replication; PRIMARY TARGET IN GRAM (-)) and TOPOISOMERASE IV (required to separate DNA into daughter cells; PRIMARY TARGET IN GRAM (+))

Question 3

Fluoroquinolones- Bactericidal or Bacteriostatic

Answer 3

Concentration-dependent bactericidal;

AUC/MIC correlates w/ efficacy

Question 4

Mechanisms of Resistance to Fluoroquinolone Abx

Answer 4

ALTERED BINDING SITES- decreased binding affinity of FQs to target sites
EXPRESSION OF ACTIVE EFFLUX- enhances transfer of FQs out of cell
ALTERED CELL WALL PERMEABILITY- decreased FQ accumulation w/i the cell (rare)
CROSS-RESISTANCE IS USUALLY OBSERVED BETWEEN THE FQs

Question 5

The Available Fluoroquinolones

Answer 5

The main question is "Do they have activity against pneumococcus?"
Older FQs: CIPROFLOXACIN
Newer FQs (Respiratory FQs):
LEVOFLOXACIN
MOXIFLOXACIN

Question 6

Fluoroquinolones Spectrum of Activity Gram (+)

Answer 6

Gram (+) Aerobes: older agents w/ poor activity; newer respiratory FQs w/ enhanced activity
STREP. PNEUMO, INCL. PRSP
MSSA (NOT MRSA)
Group & Viridans Strep (limited)
Enterococcus Spp. (limited)

Question 7

Fluoroquinolones Spectrum of Activity Gram (-)

Answer 7

Gram (-) Aerobes: some FQs have excellent activity (CIPRO=LEVO>MOXI)
PSEUDOMONAS AERUGINOSA- significant resistance has emerged, cipro & levo have best activity, NOT MOXI
Enterobacter
H. influenzae
M. catarrhalis
Neisseria spp.

Question 8

Fluoroquinolones Spectrum of Activity Anaerobes, Atypical bacteria, and others

Answer 8

Anaerobes:
ONLY MOXIFLOXACIN have adequate activity against Bacteroides spp.

Atypical bacteria: ALL FQs HAVE EXCELLENT ACTIVITY, INCL.
LEGIONELLA PNEUMOPHILA- DOC
CHLAMYDOPHILA AND CHLAMYDIA SPP.
MYCOPLASMA SPP.
UREAPLASMA UREALYTICUM

Other: TB, Bacillus anthracis

Question 9

Fluoroquinolones- PAE?

Answer 9

FQs have post-antibiotic effect for both Gram (-) and Gram (+) bacteria

Question 10

Fluoroquinolones Absorption

Answer 10

Have GOOD BIOAVAILABILITY after oral or IV administration

Question 11

Fluoroquinolones Distribution

Answer 11

Extensive distribution, incl:
LUNG
BONE
URINARY TRACT & PROSTATE (CIPRO, LEVO ONLY, THUS NOT MOXI FOR UTIS)
MINIMAL CSF PENETRATION

Question 12

Fluoroquinolones Elimination

Answer 12

Renally: CIPRO, LEVO, dosage adjustments necessary w/ renal insufficiency
Hepatically: MOXI

NONE OF THE FQs ARE REMOVED DURING HEMODIALYSIS!!!

Question 13

Fluoroquinolones Clinical Uses- Upper Respiratory Infections (Sinusitis, ABECB)

Answer 13

LEVO
MOXI
GEMI
CIPRO

Question 14

Fluoroquinolones Clinical Uses- Community-acquired pneumonia

Answer 14

LEVO
MOXI
GEMI

Question 15

Fluoroquinolones Clinical Uses- Nosocomial pneumonia

Answer 15

LEVO

CIPRO

Question 16

Fluoroquinolones Clinical Uses- Bacterial exacerbations in cystic fibrosis

Answer 16

CIPRO

Question 17

Fluoroquinolones Clinical Uses- UTIs (cystitis, pyelonephritis, prostatitis)

Answer 17

LEVO

CIPRO

Question 18

Fluoroquinolones Adverse Effects

Answer 18

G.I.
CNS
Hepatotoxicity (TROVA)
Phototoxicity (uncommon)
Cardiac (FQs USED W/ CAUTION W/ HYPOKALEMIA, CLASS III ANTIARRHYTHMICS, PREEXISTING QT PROLONGATION)
Articular Cartilage Damage
Tendonitis/Tendon Rupture
DYSGLYCEMIAS (GATI removed from market)

Question 19

Fluoroquinolones Drug Interactions

Answer 19

DIVALENT & TRIVALENT CATIONS- ALL PO FQs; IMPAIR ABSORPTION OF PO FQs, MAY LEAD TO CLINICAL FAILURE
Wafarin- ALL FQs
Theophylline & Cyclosporin- CIPRO

Question 20

Metronidazole

Answer 20

First found active against protozoa, then against anaerobes where it is still extremely useful.

Question 21

Metronidazole Mech of Action

Answer 21

INHIBITS DNA SYNTHESIS

• a prodrug activated by reduction
• selective toxicity against anaerobic and microaerophilic bacteria due to ferredoxins w/i these bacteria

Question 22

Metronidazole- Bactericidal or Bacteriostatic?

Answer 22

Concentration-dependent Bactericidal

Question 23

Mechanisms of Resistance against Metronidazole

Answer 23

ALTERED GROWTH REQUIREMENTS- organism grows in higher local oxygen [ ]s
ALTERED FERREDOXIN LEVELS

• well documented but uncommon

Question 24

Metronidazole Spectrum of Activity

Answer 24

Anaerobic bacteria:
BACTEROIDES SPP. (ALL)
CLOSTRIDIUM (ALL)
others

Anaerobic Protozoa:
Trichomonas vaginalis
Entamoeba histolytica
Giardia lamblia
Gardnerella vaginalis

Question 25

Metronidazole Absorption

Answer 25

rapidly & completely absorbed (F>90%), food has limited affect

Question 26

Metronidazole Distribution

Answer 26

DOES PENETRATE THE CSF
Good serum [ ]s PO or IV
Well absorbed into tissues & fluids

Question 27

Metronidazole Elimination

Answer 27

Liver, excreted in feces; is removed during hemodialysis

1/2 life= 6-8 hrs

Question 28

Metronidazole Clinical uses

Answer 28

ANAEROBIC INFECTIONS:

• INTRAABDOMINAL
• PELVIC
• DIABETIC FOOT & DECUBITUS ULCER INFECTIONS
• BRAIN ABSCESS (is only abx that penetrates abscesses)

PSEUDOMEMBRANOUS COLITIS DUE TO C-DIF

• METRONIDAZOLE WAS DRUG OF CHOICE, NOW INDICATED FOR MILD TO MODERATE DISEASE
• PO OR IV

Other:
- TRICHOMONAS

Question 29

Metronidazole Adverse Effects

Answer 29

G.I.: STOMATITIS, METALLIC TASTE
CNS- PERIPHERAL NEUROPATHY
Mutagenicity, carcinogenicity: AVOID DURING PREGNANCY and breastfeeding

Question 30

Metronidazole Drug Interactions

Answer 30

WARFARIN- INCREASES ANTICOAGULANT EFFECT

ALCOHOL- DISULFIRAM REACTION