Focus on FluoroQUinolones:

Facts, Questions, and

Updates
Catessa Howard, PharmD
PGY1 Pharmacy Resident
ID Case Conference
February 27. 2018
Speaker Disclosure Statement

I, Catessa Howard, have no actual or potential conflicts of interest

to disclose in relationship to this presentation.

2
Primary and Secondary Learning Objectives
1.  Review fluoroquinolone mechanisms of action, pharmacokinetics,
and pharmacodynamics
2.  Review fluoroquinolones adverse effect profile and reasons behind
the 2016 Food and Drug Administration (FDA) issued safety alerts
3.  Discuss fluoroquinolone resistance and collateral damage
4.  Discuss delafloxacin and its potential role as a new antimicrobial
agent

3
Facts: Fluoroquinolone Review
Review fluoroquinolone mechanisms of action,
pharmacokinetics, and pharmacodynamics

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 Mechanism of Action
§ Inhibits DNA gyrase and topoisomerase IV
§ DNA gyrase uncoils bacterial DNA to allow for further replication
§ Topoisomerase IV separates newly interlinked chromosomes
before cell division
§ Spectrum of activity depends on enzyme affinity

5
Peterson. Clinical Infec+ous Diseases. 2001.
 Structure-Function Relationship

R5 O

=
F CO2H

X N
R7 R2

R8 R1
Effects:
•  Potency
•  Pharmacokinetics
6
Andersson. Journal of An+microbial Chemotherapy. 2003.
 Structure-Function Relationship

R5 O

=
F CO2H

X N
R7 R2
Effects:
R8 R1 Close to DNA gyrase
binding site

7
Andersson. Journal of An+microbial Chemotherapy. 2003.
 Structure-Function Relationship Effects:
•  Bacterial transport
R5 •  DNA gyrase binding
O

=
F CO2H

X N
R7 R2

R8 R1

8
Andersson. Journal of An+microbial Chemotherapy. 2003.
 Structure-Function Relationship

Effects: R5 O

=
•  Potency
F CO2H
•  Gram-positive activity

X N
R7 R2

R8 R1

9
Andersson. Journal of An+microbial Chemotherapy. 2003.
 Structure-Function Relationship

R5 O

=
F CO2H
Effects:
•  Bacterial potency
•  DNA gyrase potency X N
R7 R2

R8 R1

10
Andersson. Journal of An+microbial Chemotherapy. 2003.
 Structure-Function Relationship

R5 O

=
F CO2H

X N
R7 R2
Effects:
•  Potency R8 R1
•  Spectrum
•  Pharmacokinetics
11
Peterson. Clinical Infec+ous Diseases. 2001.
 Structure-Function Relationship

R5 O

=
F CO2H

X N
R7 R2

Effects: R8 R1
•  Pharmacokinetics
•  Anaerobic activity
12

Andersson. Journal of An+microbial Chemotherapy. 2003.

 Pharmacodynamics
§ Concentration dependent killing
§ Major predictive parameters:
⎻ AUC/MIC: 100 – 120
⎻ Cmax/MIC: 10:1
§ Bactericidal
§ Post antibiotic effect & post antibiotic sub-MIC effect

13
Andersson. Journal of An+microbial Chemotherapy. 2003.
 Structure-Function Relationship: Ciprofloxacin

Pharmacokinetics

Frequency BID
Cmax 3.5 mg/L
AUC 30 mg h/L
Protein Bound 30%
Half-life 4h
Elimination Renal

14
Peterson. Clinical Infec+ous Diseases. 2001.
Andersson. Journal of An+microbial Chemotherapy. 2003.
 Antimicrobial Spectrum: Ciprofloxacin
Organism Ciprofloxacin Levofloxacin Moxifloxacin
MIC MIC MIC MIC MIC MIC
+/- +/- +/-
50 90 50 90 50 90

E. coli 0.03 1 +/-

Pseudomonas 1 4 --

S. pneumonaie 2 8 -- --

MSSA 1 2 --

Chlamydia spp. 0.5 2 +/-

Bacteroides 4 32 -- --
15

Andersson. Journal of An+microbial Chemotherapy. 2003.

 Structure-Function Relationship: Levofloxacin
O Pharmacokinetics

=
F CO2H
Frequency Daily
Cmax 2.5 mg/L
AUC 48 mg h/L
N
Protein Bound 30%
O Half-life 7h
Elimination Renal

16
Peterson. Clinical Infec+ous Diseases. 2001.
Andersson. Journal of An+microbial Chemotherapy. 2003.
 Antimicrobial Spectrum: Levofloxacin
Organism Ciprofloxacin Levofloxacin Moxifloxacin
MIC MIC MIC MIC MIC MIC
+/- +/- +/-
50 90 50 90 50 90

E. coli 0.03 1 +/- 0.03 0.5 +

Pseudomonas 1 4 -- 2 12 -- --

S. pneumonaie 2 8 -- -- 1 2 --

MSSA 1 2 -- 0.25 2 +/-

Chlamydia spp. 0.5 2 +/- 0.5 1 +/-

Bacteroides 4 32 -- -- 2 8 -- 17
Andersson. Journal of An+microbial Chemotherapy. 2003.
 Structure-Function Relationship: Moxifloxacin
O

=
F CO2H Pharmacokinetics
Frequency Daily
Cmax 3.1 mg/L
N AUC 30 mg h/L
Protein Bound 40%
O
Half-life 13 h
CH3 Elimination Hepatic

18
Peterson. Clinical Infec+ous Diseases. 2001.
Andersson. Journal of An+microbial Chemotherapy. 2003.
 Antimicrobial Spectrum: Moxifloxacin
Organism Ciprofloxacin Levofloxacin Moxifloxacin
MIC MIC MIC MIC MIC MIC
+/- +/- +/-
50 90 50 90 50 90

E. coli 0.03 1 +/- 0.03 0.5 + 0.03 0.06 +

Pseudomonas 1 4 -- 2 12 -- -- 2 8 -- --

S. pneumonaie 2 8 -- -- 1 2 -- 0.03 0.12 ++

MSSA 1 2 -- 0.25 2 +/- 0.12 0.6 +/-

Chlamydia spp. 0.5 2 +/- 0.5 1 +/- 0.12 1 +/-

Bacteroides 4 32 -- -- 2 8 -- 0.6 1 +/- 19

Andersson. Journal of An+microbial Chemotherapy. 2003.

 Fluoroquinolone Benefits
§ High bioavailability with easy IV:PO conversion
Drug IV PO
Ciprofloxacin 1 1.25
Levofloxacin 1 1
Moxifloxacin 1 1

20
Andriole. Yale. 2002
Assessment Question #1

Which of the following has the greatest S. pneumo coverage?

A.  Ciprofloxacin
B.  Levofloxacin
C.  Moxifloxacin
D.  None of the above

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Questions: Fluoroquinolone Adverse Events
Review fluoroquinolones adverse effect profile and reasons behind
the 2016 FDA issued safety alerts

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 FDA Safety Alerts

• Black Box warning of tendonitis and tendon rupture

2008

23
Food and Drug Administra9on. Drug Safety and Availability. 2008 .
 Fluoroquinolones and Collagen
Type I and Type III collagen comprise:
§  Majority of collagen in the Achilles tendon
§  80-90% of collagen in the aorta

Bidell. Pharmacotherapy. 36, 6. 2016. 24

Daneman. BMJ. 5, 2015.
 Fluoroquinolones and Collagen: Breakdown Mechanism
Direct tissue Release of
injury nitric oxide

Collagen Inhibition of
degrading mammalian
enzymes DNA gyrase
25
Bidell. Pharmacotherapy. 36, 6. 2016.
 Collagen Breakdown: Adverse Effects
Direct tissue Release of
injury nitric oxide
Adverse effects:
§ Tendinopathies
§ Aor9c dissec9on
§ Aor9c aneurysm

Collagen Inhibition of
degrading mammalian
enzymes DNA gyrase 26
Bidell. Pharmacotherapy. 36, 6. 2016.
 Tendinopathy

Overview Risk Factors Statistics

Age > 60 Number needed

Weight bearing to harm: 178
tendons Concomitant
steroid use Onset: 9 – 13
Renal days
Levofloxacin is dysfunction
greatest Recovery: 15 –
offender Solid organ
transplant 30 days
27
Bidell. Pharmacotherapy. 36, 6. 2016.
 Aortic Dissection (AD) and Aortic Aneurysm (AA)

Overview Risk Factors Statistics

Age > 65 Absolute risk is

moderate
Systematic Smoking
review and Number needed
meta-analysis Hypertension
to harm: 618
conducted Diabetes
Marfan’s Onset: 20 days
syndrome
28
Singh. American Journal of Medicine. 2017.
 FDA Safety Alerts

• Black Box warning of tendonitis and tendon rupture

2008

• Black Box warning of peripheral neuropathy

2013
29
Food and Drug Administra9on. Drug Safety and Availability. 2013 .
 Peripheral Neuropathy

Mechanism 2001 Data 2014 Data

Earlier data
Inhibition of suggests effects
mitochondrial are short term
DNA gyrase
78% have Fluoroquinolone
symptoms > 3 use increases
months risk by 30%
Rapid onset of
action 58% have
symptoms > 1
year
30
Etminan. American Academy of Neurology. 83. 2014.
Cohen. Annals of Pharmacotherapy. 12. 2001.
 FDA Safety Alerts
• Adverse effects significantly outweigh benefit for:
• Acute sinusitis, acute bronchitis, and uncomplicated
May urinary tract infections
2016

July • Update to Boxed Warnings and Limitations of Use

2016
31
Food and Drug Administra9on. Drug Safety and Availability. 2016 .
 Risk of Clostridium difficile Infection
Clostridium difficile
Antibiotic Hazard Ratio 95% Confidence Interval
Quinolones 4.0 2.7-5.9
3rd & 4th Gen Cephalosporins 3.1 1.9-5.2
IV Vancomycin 2.6 1.7-4.0
1st & 2nd Gen Cephalosporins 2.4 1.4-4.1
Β-Lactamase inhibitors combos 2.3 1.5-3.5
Sulfas 1.9 1.1-3.4
Clindamycin 1.9 0.8-4.4
Aminoglycoside 0.9 0.3-3.0
Metronidazole 0.3 0.1-0.9 32
Other Adverse Effects
§ Photosensitivity
§ CNS side effects
§ Dizziness, hallucinations, increased cranial pressure
§ QTc prolongation
§ Moxifloxacin > levofloxacin > ciprofloxacin
§ Myasthenia gravis exacerbation
§ Retinal detachment

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Resistance Mechanisms
§ Target enzyme modification

§ Plasmid mediated resistance

§ Decreased membrane permeability

§ Efflux pumps

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Assessment Question #2
In 2016, the FDA suggested fluoroquinolones to be avoided in
which of the following infectious diseases?
A.  Osteomyelitis
B.  Cellulitis
C.  COPD Exacerbation
D.  Pyelonephritis

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Updates: Delafloxacin
Discuss delafloxacin and its potential role as a new antimicrobial

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 Recent FDA Approval June 2017
§ Approved for acute bacterial skin and skin structure infections
(ABSSSIs)
§ Erysipelas
§ Wound infections
§ Skin abscesses
§ Cellulitis

37
.
Candel. Drug, Design, Development and Therapy. 11, 2017
 Delafloxacin: Pharmacodynamics
§ Concentration dependent killing
§ AUC/MIC is greatest predictor of bacterial eradication
Target 25-40
§ Possibly higher AUC/MIC achieved with delafloxacin

§ Bactericidal

38
.
Candel. Drug, Design, Development and Therapy. 11, 2017
 Structure and Function
O Pharmacokinetics

=
F CO2H
Frequency BID
Cmax 10.5 mg/L
AUC 26.2 mg h/L
N N
Protein Bound 84%
Cl F
OH N Half-life 10 hrs
Elimination Renal
H2N
F 39
Candel. Drug, Design, Development and Therapy. 11, 2017.
 Antimicrobial Spectrum
Organism Ciprofloxacin Levofloxacin Moxifloxacin Delafloxacin
MIC MIC MIC MIC MIC MIC MIC MIC
50 90
+/-
50 90
+/-
50 90
+/- +/-
50 90

E. coli 0.03 1 +/- 0.03 0.5 + 0.03 0.06 + 0.03 4 +/-

Pseudomonas 1 4 -- 2 12 -- -- 2 8 -- -- 0.25 4 +/-
S. pneumonaie 2 8 -- -- 1 2 -- 0.03 0.12 ++ 0.008 0.02 ++

MSSA 1 2 -- 0.25 2 +/- 0.12 0.6 +/- 0.004 0.03 ++

Chlamydia spp. 0.5 2 +/- 0.5 1 +/- 0.12 1 +/- 0.06 0.125 +/-
Bacteroides 4 32 -- -- 2 8 -- 0.6 1 +/- 0.06 0.12 +/-
MRSA 0.03 0.5 +/- 40

.
Pfaller. An+microbial Agents and Chemotherapy 2017
 Delafloxacin: Basic Drug Facts

Formulation Dosing Renal Adjustment (CrCl

< 30 mL/min)
IV 300 mg BID 200 mg BID
PO 450 mg BID 200 mg BID

41
.
Candel. Drug, Design, Development and Therapy. 11, 2017
 Delafloxacin: Adverse effects
§ Black Box Warnings:
§ Tendinopathies
§ Myasthenia gravis exacerbation
§ Peripheral neuropathy
§ Central nervous system effects

42
.
Candel. Drug, Design, Development and Therapy. 11, 2017
 Clinical Trials: Complicated Skin and Soft Tissue Infections
(SSTIs)
Study Delafloxacin (DLX) Comparator Primary Results
Outcome
Phase II IV 300 mg Q12H Tigecycline 100 Symptom Cure rate >
IV 450 mg Q12H mg load, 50 resolution 90% in all
mg Q12H three groups
Phase II IV 300 mg Q12H Linezolid 600 Signs and Significant
IV 600 mg Q12H mg Q12H symptoms difference in
resolution cure between
Vancomycin DLX and
vancomycin
O’Riordan. Int Infect Dis. 2014 43

.
Kingsley Journal of An+microbial Chemotherapy. 2016
 Clinical Trials: Complicated SSTIs, continued
Study Delafloxacin Comparator Primary Results
(DLX) Outcome
Phase III IV 300 mg Aztreonam + Reduction of Non-inferior
Q12H Vancomycin lesion size in
first 48-72
PO 450 mg hours
Q12H
Clinical
response at 28
days
44
.
Candel. Drug, Design, Development and Therapy. 11, 2017
 Clinical Trials: Acute COPD Exacerbation
Study Delafloxacin Comparator Primary Results
(DLX) Outcome
Phase II 200 mg daily Levofloxacin Resolution of Equivalent
for 5 days 500 mg daily symptoms effectiveness
for 7 days

45
Longcor. ID Week. 2012
Delafloxacin’s Potential Role

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Delafloxacin’s Potential Role
§ Approved for a condition in which many treatment options exist

§ Wide spectrum of activity

§ Compared against very broad antimicrobials

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Assessment Question #3
Delafloxacin has NOT been studied for which of the following
infectious diseases?
A.  SSTIs
B.  Community Acquired Pneumonia
C.  Endocarditis
D.  COPD exacerbation

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Summary
§ Fluoroquinolones should be reserved for patients with no other
viable, effective options

§ Communicate evidence behind choosing alternative agents over

fluoroquinolones

§ Delafloxacin is a new, broad spectrum antimicrobial agent with

great potential for overuse

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Focus on FluoroQUinolones:
Facts, Questions, and
Updates
Catessa Howard, PharmD
PGY1 Pharmacy Resident
Pharmacy Grand Rounds
10/31/2017