Title: PharmaNote
ALL VOLUMES CITATION PDF VIEWER THUMBNAILS PAGE IMAGE ZOOMABLE
Full Citation
STANDARD VIEW MARC VIEW
Permanent Link: http://ufdc.ufl.edu/UF00087345/00015
 Material Information
Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: September 2003
 Record Information
Bibliographic ID: UF00087345
Volume ID: VID00015
Source Institution: University of Florida
Rights Management: All rights reserved by the source institution and holding location.

Downloads

This item has the following downloads:

September2003 ( PDF )


Full Text















GEMIFLOXACIN (FACTTV)
DUAL-TARGETING
FLUOROQUINOLONE

Melissa Kuznik, Pharm.D. Candidate



Introduction
Since 1962, when the first quinolone pre-
cursor was discovered, fluoroquinolones (FQ) have
become an important antibiotic class. Initially, they
offered strong coverage against gram-negative bac-
teria. But with modifications, newer agents offer
coverage against both gram-negative and gram-
positive organisms. In April 2003, GeneSoft re-
ceived FDA approval to market gemifloxacin
(Factive). The approved indications include com-
munity-acquired pneumonia (CAP) and acute exac-
erbation of chronic bronchitis (AECB). This article
will review some current concepts of FQ resistance,
as well as, the pharmacology/pharmacokinetics,
dosing, clinical trials, role in therapy, and safety
profile of gemifloxacin.

Fluoroquinolone Resistance
Historically, fluoroquinolones' nitch in the
infectious disease arena was in the treatment of
urinary tract infections. However, with newer
agents offering better systemic absorption, the role
of fluoroquinolones has expanded. Today, they are
commonly used in treating gastrointestinal
infections, respiratory tract infections, sexually
transmitted diseases, and chronic osteomyelitis1.
However, inappropriate use of fluoroquinolones in
the past decade has led to the development of


bacterial resistance. In a study by Zhang et al., S.
aureus, S. epidermidis, and E. faecalis resistance to
ciprofloxacin increased by 12.2%, 27.8%, and
23.3%, respectively from 1997-2000.2 The
PROTEKT US study revealed 11 fluoroquinolone
resistant pneumococci strains in North America,
while the SENTRY study showed that 29% of the
P. aeruginosa strains in North America were
resistant to ciprofloxacin.3'4
Fluoroquinolone resistance can be
chromosomally mediated with mutations observed
in the target genes topoisomerase II and IV. Target
genes for topoisomerase II which is also called
DNA gyrase, are gyrA and gyrB, while target genes
for topoisomerase IV are parC and parE. Cross-
resistance is high among the fluoroquinolone class
as a bacterium develops resistance at either of these
sites. Another mode of resistance involves the
amount of drug actually accumulating inside the
bacteria. This is due to the bacteria developing an
impermeable membrane and/or over expressing
efflux pump systems.1'5 More recently, mobile
elements have been shown to carry a gene (qnr)
that confers resistance to fluoroquinolones; this has
the potential to introduce a new mode of resistance,
one that is plasmid mediated instead of
chromosomally mediated.5



INSIDE THIS ISSUE:

GEMIFLOXACIN (FACTIVE)
DUAL-TARGETING FLUOROQUINOLONE

WHAT PRACTITIONERS SHOULD KNOW ABOUT
THE NEW JNC 7 HYPERTENSION GUIDELINES
I -rFi


m
Pha rma Note Volume 18, Issue 12 September 2003


SPharmaNote


VOLUME 18, ISSUE 12 SEPTEMBER 2003
tlL


PharmaNote


Volume 18, Issue 12 September 2003







Table 1. Community acquired pneumonia studies evaluating gemifloxacina
D g R n Success Rate Treatment Difference
Drug Regimen (%) (95% CI)
Study 011
Gemifloxacin 320 mg x 7 days 88.7 1.1 (-7.3, 9.5)
Amoxacillin/clavulanate 500 mg/125 mg TID x 7 days 86.7
Study 061
Gemifloxacin 320 mg x 7 days 91.7 (86.1, 95.2)
Study 267
Gemifloxacin 320 mg x 7 days 89.9 (84.9-94.7)
aAll studies used a fixed 7-day antibiotic treatment regimen. CI confidence interval, TID three times daily.


Disease States
Lower respiratory tract infections are a
major cause of death. They rank number six as the
most common cause of death in the US and have
the highest mortality rate of all infections.6
Community-acquired pneumonia is associated with
a mortality rate of -14% for patients who require
hospitalization and a mortality rate of <1% for
those who do not.' Patients who suffer from
chronic obstructive pulmonary disease (COPD)
often experience AECB. Viruses are most
commonly responsible for these exacerbations, so
antibiotic use in this infection is controversial.8
The most common pathogens encountered
in CAP and AECB are S. pneumoniae, H.
influenza, M. catarrhalis, C. pneumoniae, M.
pneumoniae, and Legionella species.8'9 The 2000
Infectious Diseases Society of America (IDSA)
guidelines recommend a fluoroquinolone as first-
line treatment/alternative for CAP in almost all
patients over 18 years old. On the other hand, the
2003 Antibacterial Selection for CAP (ASCAP)
and the Centers for Disease Control and Prevention
(CDC) guidelines recommend restricting the use of
fluoroquinolones to limit resistant strains from
emerging.7'9'10 Instead they recommend using a
third generation cephalosporin along with a
macrolide. Furthermore, when an antibiotic is
used, it should be in a patient in which an infection
has been proven or is strongly suspected to be
caused by bacteria that is susceptible to the
antibiotic chosen.

Gemifloxacin
Gemifloxacin is one of the only fluoroqui-
nolones that target both topoisomerase II and
topoisomerase IV. By doing so, it requires a


stepwise mutation in the bacteria in order for
resistance to occur. Initially, P. aeruginosa
resistance was found to be associated with a
mutation at gyrA. However, some highly resistant
strains have also shown to possess a mutation at
parC.12 Likewise, some strains of S. pneumoniae
have shown to possess mutations at both
topoisomerase II and IV and are resistant to most
fluoroquinolones. However, gemifloxacin can
inhibit both enzymes at therapeutically acceptable
concentrations rendering some of these double
mutant strains susceptible.11

Indications
In April 2003, the FDA approved gemiflox-
acin for the treatment of mild-to-moderate CAP and
AECB. More recently, it was approved to treat
mild-to-moderate CAP due to multi-drug resistant
Streptococcus pneumoniae (MDRSP).

Pharmacology and Pharmacokinetics
Unlike most fluoroquinolones, gemifloxacin
targets both topoisomerase II and IV. These are
two enzyme systems involved in the repair and
replication of DNA. Topoisomerase II is
responsible for the supercoiling of the DNA while
topoisomerase IV aids in DNA replication by
allowing the DNA strand to separate. The
structures of the newer fluoroquinolones have an
improved affinity for topoisomerase IV, rendering
them more efficacious against gram-positive
organisms, yet maintaining their coverage vs. gram-
negative bacteria.
Gemifloxacin exhibits linear
pharmacokinetics up to a dose of 640 mg, which is
twice the daily dose for adults. It is quickly
absorbed from the gastrointestinal (GI) tract, with a


Pha rma Note Volume 18, Issue 12 September 2003


PharmaNote


Volume 18, Issue 12 September 2003







Table 2. AECB Clinical Studies evaluating gemifloxacin vs. alternative antibiotic regimens
g R n Success Rate Treatment Difference
Drug Regimen (%) (95% CI)


Study 68
Gemifloxacin 320 mg x 5 days
Clarithomycin 500 mg BID x 7 days
Study 70
Gemifloxacin 320 mg x 5 days
Amoxacillin/clavulanate 500 mg/125 mg TID x 7 days
Study 212
Gemifloxacin 320 mg x 5 days
Levofloxacin 500 mg x 7 days
CI confidence interval, BID twice daily, TID-three times daily


bioavailability of 71% and a peak concentration of
0.5-2 hours after administration. Distribution is
wide, with concentrations in bronchoalveolar
macrophages, epithelial lining fluid, and bronchial
mucosa being 90, 2, and 7 times that of plasma,
respectively. The volume of distribution is ap-
proximately 4.18 L/kg. About 60-70% of the drug
is bound to proteins and because it is only
metabolized to a limited extent by the liver,
CYP450 drug-drug interactions are not expected.
Gemifloxacin is mainly excreted in the feces and
urine with a half-life of approximately 8 hours.
No dosage adjustments are needed based on
a patient's age, hepatic, and/or renal function. How-
ever, it should not be given to those <18 yo or in
patients with a CrCl <40 ml/min. Gemifloxacin
can be taken without regard to meals. Aluminum-
and magnesium-containing antacids, ferrous
sulfate, MVI with zinc and other metallic cations,
sucralfate, and didanosine must be taken two hours
prior or three hours following gemifloxacin.
Conversely, calcium carbonate does not
significantly decrease the AUC when given
simultaneously with gemifloxacin. At this time,
there are no known clinically significant drug
interactions that require dose modifications.

Clinical Trials
In CAP, there are 3 double-blind, random-
ized, actively controlled clinical studies, 1 open, ac-
tively controlled study, and 2 uncontrolled studies.
The studies evaluated patient response to treatment,
with success defined as favorable clinical response
at follow-up. While all of the studies were suppor-


86.0
84.8


93.6
93.2


88.2
85.1


1.2 (-4.7, 7.0)



0.4 (-3.9, 4.6)



3.1 (-4.7, 10.7)


tive, only one of the double-blind studies and 2 un-
controlled studies used a strict 7-day dosing pattern
(Table 1). No p-values were provided, only confi-
dence intervals.11
Clinical trials for AECB included three dou-
ble blind, randomized, actively controlled studies.
Success rate was again determined by clinical re-
sponse at follow-up (Table 2).11

Toxicity and Safety
The manufacturer has not provided docu-
mentation comparing gemifloxacin's side effect
profile to that of placebo. However, common side
effects of gemifloxacin compared to other antibiot-
ics are listed in Table 3. Most of the side effects
were considered mild to moderate in severity, with
rash being the most common especially in females
<40 years of age. To lessen the chance of side ef-
fects, it is important that gemifloxacin only be used
for the recommended length of time.

Dosing and Administration
Gemifloxacin will be supplied as a 320 mg
oral tablet in five- and seven-day dose packs. It is
dosed once daily for seven days for CAP and once
daily for five days for AECB. Gemifloxacin should
be taken with plenty of liquid and can be taken
without regard to meals. Dosing adjustments are
only required in patients whose CrCl is <40 ml/min
or those undergoing dialysis; the dose for these pa-
tients should be 160 mg per day. This drug should
not routinely be used and has not been approved for
use in patients younger than 18 years of age or
pregnant/lactating women.11


Pha rma Note Volume 18, Issue 12 September 2003


PharmaNote


Volume 18, Issue 12 September 2003








Table 3. Comparison of side effects of gemifloxacin to other oral antibiotics
Gemifloxacin 320 mg Oral Antibiotic Comparators*
Side Effect
Side Effe(% patients) (% patients)
Diarrhea 3.6 4.6
Rash 2.8 0.6
Nausea 2.7 3.2
Headache 1.2 1.5
Abdominal Pain 0.9 1.1
Vomitting 0.9 1.1
Dizziness 0.8 1.5
Taste Perversion 0.3 1.9
* included B-lactam, macrolide, and other fluoroquinolone antibiotics


Cost
The retail cost of gemifloxacin was not
available at the time this article was prepared.

Summary
Since the discovery of fluoroquinolones,
their use has played a major role in combating in-
fections. However, with their extensive use has
come misuse that has led to resistance at target
genes within bacteria5. Gemifloxacin is the newest
addition to this class. It works at both topoisom-
erase II and IV and has demonstrated to be effec-
tive in the treatment of both CAP and AECB.

References
1. Chen, FJ et al. Molecular mechanisms of fluoroqui-
nolone resistance. J Microbiol Immunol Infect 2003
Mar;36(1):1-9.
2. Zhang, YL et al. Survey on drug resistance to ciproflox-
acin in common pathogenic bacteria. Dept of Infection
Control, Nanfang Hospital, First Military Medical Uni-
versity, Guangzhou, China. Apr 2002.
3. Hoban, D. et al. Antimicrobial susceptibility of commu-
nity-acquired respiratory tract pathogens in North Amer-
ica in 1999-2000: findings of the PROTEKT surveil-
lance study. Diagn Microbiol Infect Dis 45 (2003): 251-
259.
4. Gordon KA et al. Susceptibility patterns of orally admin-
istered antimicrobials among urinary tract infection
pathogens from hospitalized patients in North America:
comparison report to Europe and Latin America. Results
form the SENTRY Antimicrobial Surveillance Program
(2000). Diagn Microbiol Infect Dis. 2003 Apr; 45 (4):
295-301.
5. Ruiz, J. Mechanisms of resistance to quinolones: target
alterations, decreased accumulation and DNA gyrase pro-
tection. J Antimicrobial Chemotherapy 2003;51: 1109-
1117.
6. Patterson, JE. The role of new quinolones in treating pul-
monary infection. American College of Chest Physi-
cians. Available from URL: http \ "\.chestnet.org/


education/online/pccu/voll4/lessonl7 18/lessonl8.php
(Accessed 7/16/2003).
7. Bartlett, JG et al. Practice guidelines for the management
of community-acquired pneumonia in adults. Clinical
Infections Diseases 2000; 31: 347-82.
8. The Alberta Clinical Practice Guidelines Program.
Guideline for the management of acute exacerbation of
chronic bronchitis. Alberta Medical Association. Nov
2001. Available from URL: www.albertadoctors.org.
9. Hospital Medicine Consensus Report. Community-
acquired pneumonia: Evidence-based antibiotic selection
and outcome-effective patient management-year 2003
update. Year 2003 ASCAP Panel Consensus Report.
Available from URL: http://www.ahcpub.com/
ahc root html/hot/archive/ascap2003.pdf
10. Heffelfinger JD et al. Management of community-
acquired pneumonia in the era of pneumococcal resis-
tance. Arch of Intern Med 2000; 160: 1399-1408.
11. Factive [Package insert]. GeneSoft; 2003.
12. Higgins PG et al. Mutations in GyrA, ParC, MexR, and
NfxB in clinical isolates of Pseudomonas aeruginosa. Int
J Antimicrob Agents 2003 May; 21(5): 409-413.



The PharmaNote is Published by:
The Department of Pharmacy Services,
UF Family Practice Medical Group,
Departments of Community Health
and Family Medicine and Pharmacy
Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor
Pharm.D.


-
Pha rma Note Volume 18, Issue 12 September 2003


PharmaNote


Volume 18, Issue 12 September 2003








WHAT PRACTITIONERS
SHOULD KNOW ABOUT THE
NEW JNC 7 HYPERTENSION
GUIDELINES


John M. Tovar, Pharm.D.


Introduction
Hypertension affects approximately 50 mil-
lion individuals in the United States and over 1 bil-
lion worldwide.1 The relationship between blood
pressure and risk of cardiovascular disease (CVD)
is well-established with numerous clinical studies
demonstrating that blood pressure is a continuous,
consistent, and independent risk factor of CVD.
The benefits of lowering blood pressure are
also well-established. In clinical trials, antihyper-
tensives have been shown to decrease the incidence
of stroke (35-40%), myocardial infarction (20-
25%), and heart failure (50%). Unfortunately,
blood pressure control rates are far below the
Healthy people 2010 goal of 50%. The National
Health and Nutrition Examination Survey
(NHANES) for the 1999-2000 period reported that
although 68.9% of people were aware of their hy-
pertension, only 58.4% were treated and hyperten-
sion was controlled in only 31% of individuals.2


JNC 7
Since the "Sixth Report of the Joint Na-
tional Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure
(JNC 6)" was released in 1996, many large-scale
clinical trials have been published. Therefore, the
National High Blood Pressure Education Program
(NHBPEP) and the National Heart, Lung, and
Blood Institute (NHLBI) deemed necessary the
publication of a new set of guidelines that would
simplify the classification of blood pressure as well
as provide new, clear, and concise recommenda-
tions for the management of hypertension.1
In order to facilitate its implementation, the
"Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treat-
ment of High Blood Pressure (JNC 7)" will be pre-
sented in 2 separate publications. The first or
"Express," which is a succinct and practical guide
for the busy practitioner, was released in May of
2003. This will be followed by a more comprehen-
sive report that will contain a detailed review of the
current recommendations and is expected to be re-
leased sometime in the Fall of 2003.3

Key Messages
1. In persons older than 50 years, systolic blood
pressure greater than 140 mmHg is a much
more important CVD risk factor than diastolic


Table 1. Classification and management of blood pressure for adults*

Initial Drug Therapy
BP SBP* DBP Lifestyle Initl D g
Classification (mmHg) (mmHg) Modification Without Compelling With Compelling
Indication Indications
Normal <120 and <80 Encourage No antihypertensive indicated. Drugs for compelling indications.T
Prehypertension 120-139 or 80-89 Yes No antihypertensive indicated. Drugs for compelling indications.
Stage 1 140-159 or 90-99 Yes Thiazide-type diuretics for most. Drug(s) for the compelling indica-
Hypertension May consider ACEI, ARB, BB, tions.1 Other antihypertensive
CCB, or combination, drugs (diuretics, ACEI, ARB, BB,
CCB) as needed.
Stage 2 =160 or =100 Yes Two-drug combination for most Drug(s) for the compelling indica-
Hypertension (usually thiazide-type diuretic tions. Other antihypertensive
and ACE, ARB, BB, or CCB). drugs (diuretics, ACEI, ARB, BB,
CCB) as needed.


DBP diastolic blood pressure; SBP systolic blood pressure
Drug abbreviations: ACEI=angiotensin converting enzyme inhibitor; ARB angiotensin receptor blocker; BB beta-blocker; CCB calcium channel blocker.
STreatment determined by highest BP category. For compelling indications refer to Table 2.
Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.
I Treat patients with chronic kidney disease or diabetes to BP goal of 130/80 mmHg.

armalntm V \/nlllmn 1 I Q lel 10 tC mhn r O n


Dh


03


I I I I I I IU I W


v luIllll ..u I *u 1 .L V--^ 1k 111I Vp i .








Table 2. Compelling indications for individual drug classes

Recommended Drugst
Compelling Indication" Recomm d
Diuretic BB ACEI ARB CCB Aldo ANT

Heart Failure X X X X X

Postmyocardial infarction X X X

High coronary disease risk X X X X

Diabetes X X X X X

Chronic kidney disease X X

Recurrent stroke prevention X X

Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is man-
aged in parallel with the BP.
SDrug abbreviations: BB beta-blocker; ACEI=angiotensin converting enzyme inhibitor; ARB angiotensin receptor blocker; CCB calcium channel blocker;
Aldo ANT aldosterone antagonist.


blood pressure.
2. The risk of CVD begins at 115/75 mmHg and
doubles with each increment of 20/10 mmHg.
3. Individuals who are normotensive at age 55
have a 90% lifetime risk of developing hyper-
tension.
4. The classification of blood pressure has been
simplified (Table 1), with prehypertensive pa-
tients requiring health-promoting lifestyle
modifications to prevent CVD.
5. Thiazide-type diuretics should be used for most
patients with uncomplicated hypertension, ei-
ther alone or combined with drugs from other
classes. Certain high-risk conditions are com-
pelling indications (Table 2) for the initial use


Lifestyle Modificaons

Not at Goal Blood Pressure (14090 mmHg)
(<13080 mmHgfor those th diabetes orchronic ldney disease)

Inibal Drug Choices
I


VWthoutCompelling
Indicabons

Stage Hypertension Stage 2 Hypertension
(SBP 140-159 or DBP 90-99 mmHg) (SBP S 160 or DBP >100 mmHg)
Thide-type durebcs formost 2dug oImbinaon formost(usually
May nsiderACEI RB BB CCB or ACadtypedurebcand
cmbinabon ACEI orAPB orBB orCCB)
II


S Wih Compelling
Indications

Drug(s)forthe compelling
indicatons
Otheranthypertensive drugs
(diuretics ACEI ARB BB CCB)
as needed


Figure 1. Algorithm for the treatment of hypertension.


of other antihypertensive drug classes
(angiotensin converting enzyme inhibitors, an-
giotensin receptor blockers, beta-blockers, cal-
cium channel blockers).
6. Most patients with hypertension will require
two or more antihypertensive medications to
achieve goal blood pressure (<140/90 mmHg,
or <130/80 mmHg for patients with diabetes or
chronic kidney disease).
7. If blood pressure is >20/10 mmHg above goal,
consideration should be given to initiating ther-
apy with two agents, one of which usually
should be a thiazide-type diuretic.
8. The most effective therapy prescribed by the
most careful clinician will control hypertension
only if patients are motivated. Motivation im-
proves when patients have positive experiences
with, and trust in, the clinician. Empathy builds
trust and is a potent motivator.


References
1. National Heart, Lung, and Blood Institute. JNC 7 Ex-
press: The Seventh Report of the Joint National Commit-
tee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure. National Institutes of Health
May 2003. Available from URL: http://www.nhlbi.nih.
gov/guidelines/hvpertension/express.pdf.
2. Hajjar I, Kotchen TA. Trends in Prevalence, Awareness,
Treatment, and Control of hypertension in the United
States, 1988-2000. JAMA 2003;290(2):199-206.
3. Chobanian AV, Bakris GL, Black HR, et al. The Seventh
Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood
Pressure. JAMA 2003;289(19):2560-72.


Pha rma Note Volume 18, Issue 12 September 2003


PharmaNote


Volume 18, Issue 12 September 2003




University of Florida Home Page
© 2004 - 2010 University of Florida George A. Smathers Libraries.
All rights reserved.

Acceptable Use, Copyright, and Disclaimer Statement
Last updated October 10, 2010 - - mvs