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Creator: University of Florida College of Pharmacy
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Publication Date: September 2005
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TREATING HEART FAILURE IN
AFRICAN AMERICANS: FOCUS
ON BIDIL

E. Loveta Epie, Pharm.D.



Heart failure (HF) is a progressive syn-
drome characterized by dyspnea, fatigue, and fluid
overload. It affects about 6 million Americans and
over half of this population dies within a few years
of being diagnosed.1 African Americans (AA) usu-
ally present with HF at a younger age, are affected
approximately twice as often as other ethnic groups
and are more likely to die from HF. Despite the
success of conventional treatment options, includ-
ing angiotensin converting enzyme (ACE) inhibi-
tors and P-blockers, morbidity and mortality from
HF remains high, especially in AA.
The hallmark of this syndrome is left ven-
tricular dysfunction (LVD), which leads to de-
creased cardiac output (CO). A reduction in for-
ward flow of blood activates a number of systemic
and local compensatory responses. Ventricular dila-
tion and hypertrophy occur in an attempt to in-
crease diastolic filling capacity and increase CO. In
addition to mechanical stretch, neuro-hormonal
adaptive mechanisms also contribute to heart fail-
ure. These are mainly mediated by the sympathetic
nervous system (SNS) and the renin-angiotensin-
aldosterone system (RAAS).1
Heart failure is typically treated with ACE
inhibitors, but in African Americans the RAAS ap-


pears to play a less significant role, thus ACE inhibi-
tors and other drugs that modulate the RAAS may
be less effective than in other populations.2 Some
studies have suggested a lower response in African
Americans to ACE inhibitors,3'5 whereas others have
not.6 African Americans due seem to exhibit lower
levels of nitric oxide in their coronary and peripheral
vasculature. This observation suggests that African
Americans may be more responsive to nitric oxide
replacement than other races.
The combination of hydralazine and nitrates
was used to mange CHF before the advent of ACE
inhibitors and angiotensin receptor blockers (ARBs).
Presently, the combination is reserved for patients
intolerant of more conventional pharmacologic
agents. BiDil, a fixed dose combination of hydra-
lazine and isosorbide dinitrate (Hyd-ISDN), has been
developed by NitroMed for the treatment of African
Americans with HF. The drug was approved by the
FDA in June 2005 and the 37.5/20 mg (hydralazine/
ISDN) strength used in the African American Heart
Failure Trial (A-HeFT) trial was made available for
prescription in July 2005.9 This article will examine
the efficacy and safety of Hyd-ISDN and explore its
role in clinical practice.

Pharmacology and Pharmacokinetics
Hydralazine is a peripheral, direct-acting


INSIDE THIS ISSUE:

TREATING HEART FAILURE IN AFRICAN
AMERICANS: FOCUS ON BIDIL
TYGACILTM: A NEW BROAD-SPECTRUM
ANTIBIOTIC
l,^


PharmaNote


VOLUME 20, ISSUE 12 SEPTEMBER 2005
Ti r








Table 1. Clinical trials of hydralazine/isosorbide dinitrate combination therapy in patients with HF.1


N Design


Study drug/
dose


Comoarator


Results


630 RDB Hyd-ISDN
300/160 mg


789 RDB


Enalapril 20 mg


1996 Cohort Enalapril 20mg






Hyd-ISDN
37.5/20mg three
1050 RDB times daily ti-
trated to 2 tab-
lets three times
daily


Prazosin
20 mg/placebo


Mortality in AA = 9.7% in
Hyd-ISDN group and 17.3% in
placebo group (p=0.04).
Whites 16.9% vs 18.8% in
placebo


Annual mortality rate was not
different in black patients
treated with enalapril (12.8%)
compared to those treated with
Hyd-ISDN Hyd-ISDN (12.9%). White
300/160 mg patients treated with enalapril
showed decrease in mortality
(11%) compared to those
treated with Hyd-ISDN
(14.9% -p=0.02)


Placebo









Placebo


Black patients randomized to
enalapril had more hospitaliza-
tions than white patients
(p=0.001). Black patients ran-
domized to placebo had simi-
lar rates of hospitalization
compared to whites (p=0.06).
Mortality was similar in both
racial groups regardless of
treatment.
43% reduction in all-cause
mortality (p=0.01) in Hyd-
ISDN group compared with
placebo in addition to standard
HF therapies. First hospitaliza-
tion rate due to HF decreased
33% in the Hyd-ISDN group
compared to placebo (p
0.001)


V-HeFT I
(1986)11


RDB denotes a randomized, double-blind trial design. NO denotes nitric oxide.


vasodilator, which induces relaxation of arteriolar
muscles resulting in afterload reduction. Hydra-
lazine's onset of action following oral administration
is 20-30 minutes; bioavailability is 30-50% in fast
acetylators and food reportedly enhances its absorp-
tion.8 Hydralazine is about 90% protein bound and
metabolized by hepatic acetylation. It is excreted
really with a 1.75-hour elimination half-life in HF
patients with normal renal function, and 14% is ex-
creted as unchanged drug. Renal impairment pro-
longs the half-life and results in higher hydralazine
plasma concentrations.8 Dosage adjustment is indi-


cated when creatinine clearance is below 50 ml/min.
ISDN is converted to nitric oxide, which
stimulates synthesis of cyclic guanosine monophos-
phate (cGMP). cGMP reduces intracellar calcium
concentrations resulting in vasodilatation via relaxa-
tion of smooth muscle cells and a decrease in pre-
load. The oral bioavailability of ISDN is approxi-
mately 58% and absorption is reduced if taken with
food. Its onset of action is about 15 minutes follow-
ing oral administration with a duration of action of
four to six hours.8 The drug is extensively metabo-
lized hepatically to active metabolites, such as the 5-


Conclusions


Hyd-ISDN showed
significant mortality
benefit among black
patients, indicating
possible NO deficiency
in this population.

Compared with hyd-
ISDN, white popula-
tion experienced sur-
vival benefit with
enalapril, but AA ex-
perienced similar mor-
tality with enalapril
and Hyd-ISDN, indi-
cating a greater re-
sponse to Hyd-ISDN,
lesser response to ACE
inhibition, or both.

Enalapril therapy
seems to be associated
with decrease in the
risk of hospitalization
among white patients
with LVD but not in
black patients.



Mortality reduction is
consistent with the
existence of another
mechanism which
controls HF progres-
sion besides neurohor-
monal mediators


V-HeFT II
(1991)12









Exner et al.
(2001)"








A-HeFT
(2005)3


c







Table 2. Adverse effects associated with hydralazine and ISDN.1's

Cardiovascular Gastrointestinal Dermatologic Misc
Tachycardia Constipation Lupus-like syndrome (dose-
Hydralazine Angina Anorexia Rash (rare) related)
Hypotension (rare) Nausea, vomiting, diarrhea Headache
Tachycardia Nausea Headache (common)
ISDN Flushing Vomiting Rash (rare) Cold sweat
Postural hypotension Bowel incontinence Syncope (rare)


mononitrate and 2-mononitrate. Half-lives for parent
drug and metabolites are 4 hours and 5 hours, respec-
tively. Elimination is virtually completely via me-
tabolism and no dosage adjustment is necessary in
the setting of renal impairment.
Growing evidence suggests that nitric oxide
plays a pivotal role in the pathophysiology of CHF
and cardiac remodeling, and impaired availability of
nitric oxide occurs in various models ofHF.3 ISDN
serves as a nitric oxide donor and hydralazine acts as
an antioxidant which prevents the breakdown of ni-
tric oxide by inhibiting the formation of reactive
oxygen radicals, including superoxide.10 Theoreti-
cally, this tandem process should be useful consider-
ing that excess superoxide reacts directly with nitric
oxide and disrupts its signaling capacity while pro-
ducing other toxic, reactive species in the process.

Clinical Trials
Some studies have demonstrated a racial dif-
ference in response to ACE inhibitors.4'5 Exner et al.
compared the response of enalapril in blacks and
whites with HF and found that enalapril was associ-
ated with a significant decrease in hospitalization in
caucasians with LVD but not in AAs.6 (Table 1)
The Vasodilator-Heart Failure Trial (V-
HeFT ) demonstrated that the combination of hyd-
ISDN decreased mortality in patients with HF.1
(Table 1) The first V-HeFT I study was conducted
between 1980 and 1985 with 450 white male patients
and 180 African American male patients who were
randomized to hyd-ISDN 300/160 mg daily, prazosin
20mg daily or placebo. There was a significant de-
crease in mortality in the group of patients treated
with hyd-ISDN compared to no change in the pre-
zosin or placebo-treated groups. However, overall, in
V-HeFT-II, patients randomized to enalapril experi-
enced greater survival compared with hyd-ISDN.12
Retrospective analyses of the V-HeFT data have sug-


gested that Caucasians respond best to inhibition of
the renin-angiotensin system, whereas Afircan
Americans are more responsive to nitric oxide re-
placement. Nevertheless, in the wake of V-HeFT-II
and subsequent studies with ACE inhibitors, Hyd-
ISDN became an alternative for patients unable to
tolerate ACE inhibitor therapy.
The A-HeFT trial was a phase III confirma-
tory study of a fixed-dose combination of hydra-
lazine and isosorbide dinitrate.3 It demonstrated that
when administered with conventional HF therapies
like P-blockers, angiotensin receptor blockers
(ARBs), ACE inhibitors, spironolactone, diuretics or
digoxin, hyd-ISDN decreases morbidity and mortal-
ity in African Americans with HF. The study was a
randomized, double blind, placebo-controlled trial
with 1050 self-identified AAs men and women with
decreased ejection fraction, left ventricular hypertro-
phy, and class NYHA III and IV HF. Treatment in-
cluded either hyd-ISDN or placebo in addition to
background therapy for HF. The dose was 37.5 mg
hydralazine and 20 mg ISDN as one tablet adminis-
tered three times daily, titrated up to two tablets three
times daily (225/120 mg daily) as tolerated.3 The pri-
mary endpoint was a composite of weighted values
for any-cause death, first hospitalization for HF dur-
ing the 18-month follow-up period, and change in
quality of life after 6 months as assessed by the Min-
nesota Living with Heart Failure questionnaire.3 The
study was originally designed to continue until early
2005 but was halted prematurely in July 2004 due to
significant survival benefit observed in the treatment
group compared to placebo.

Safety and Toxicity
The most common adverse events among pa-
tients treated with BiDil in A-HeFT were headache
(47.5%) and dizziness (29.3%) which occurred sig-
nificantly more frequently in the group given hyd-







ISDN. HF exacerbations were more frequent and
severe in the placebo group. The trial data did not
address whether or not these side effects were dose-
related. Hydralazine can cause a clinical syndrome
similar to systemic lupus erythematosus (SLE). In
patients who develop symptoms suggestive of SLE,
monitoring of complete blood counts and ANA
titers is warranted. Table 2 lists other side effects
encountered with hydralazine and ISDN.

Dosing and Monitoring
BiDil should be initiated at 1 tablet (37.5
mg hydralazine/20 mg ISDN) three times daily and
titrated up to 2 tablets three times daily (225/120
mg daily).3 There are no recommended dosage ad-
justments in patients with renal or hepatic impair-
ment.

Cost
The cost for a 180-count bottle (2 tablets
three times daily) of BiDil is $324 ($1.80/tablet).
However, BiDil will be made available by Ni-
troMed under a novel pricing structure. NitroMed
has announced that patients without insurance
whose incomes are up to 3 times the poverty level,
will be able to acquire BiDil free of charge. For
those without insurance, the cost will be approxi-
mately $25/month. Thus, most patients should be
able to access the medication at a reasonable cost.

Summary
Based on the theory that the progression of
HF may involve both neurohormonal pathways and
the nitroso-redox balance in the cardiovascular sys-
tem, the hyd-ISDN combination therapy appears to
be an effective agent for the treatment of patients
self-identified as blacks with NYHA class III or IV
HF when used in conjunction with their current HF
therapies. Considering that there is still controversy
about whether or not a racial difference in response
to conventional therapies exists, there is a need to
conduct studies in other populations of patients. For
now, BiDil is a welcomed addition to the pharma-
cological repertoire with the potential to further re-
duce mortality in African Americans with HF.

References
1. Nolan PE Jr., Zarembski DG. Congestive Heart Failure.
In: Herfindal ET, Gourley DR, editors. Textbook of
Therapeutics: Drug Disease Management. 7th ed. Mary-
land: Lippincott Williams & Wilkins; 2000: 825-66.


2. Scott RL. Is Heart Failure in African Americans a Distinct
Entity? CHF 2003;9:193-196.
3. Taylor AL, Ziesche S, Yancy C, et al. Combination of
Isosorbide Dinitrate and Hydralazine in Blacks with Heart
Failure (A-HeFT trial). N Engl J Med 2004;351:2049-57.
4. The SOLVD Investigators. Effect of Enalapril on Survival
in Patients with Reduced Ventricular Ejection Fractions
and Congestive Heart Failure. N Engl J Med
1991;325:293-302.
5. The SOLVD Investigators. Effect of Enalapril on Mortal-
ity and the Development of Heart Failure in Asympto-
matic Patients with Reduced Left Ventricular Ejection
Fractions. N Engl J Med 1992;327:685-91.
6. Exner DV, Dries DL, Domanski MJ, et al. Lesser Re-
sponse to Angiotensin-Converting Enzyme Inhibitor Ther-
apy in Blacks as Compared to White Patients with Left
Ventricular Dysfunction. N Engl J Med 2001;344:1351-
1357.
7. Dries DL, Exner DV, Gersh BJ, et al. Racial Differences
in the Outcome of Left Ventricular Dysfunction. N Engl J
Med 1999;340:609-616.
8. Micromedex Healthcare Series (2005): http://
thomsonhc.com
9. Prescription Solutions. Available at
http://www.RxSolutions.com/rxnews.asp
10. Hare JM. Nitroso-Redox Balance in the Cardiovascular
System. N Engl J Med 2004;351:2112-14.
11. Cohn JN, Archibald DG, Ziesche S, et al .Effect of vaso-
dilator therapy on mortality in chronic congestive heart
failure. Results of a Veterans Administration Cooperative
Study. N Engl J Med 1986;314:1547-52.
12. Cohn JN, Johnson G, Ziesche S, et al A comparison of
enalapril with hydralazine-isosorbide dinitrate in the treat-
ment of chronic congestive heart failure. N Engl J Med
1991;325:303-10.




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

Benjamin J. Epstein Assistant Editor
Pharm.D.









TYGACILM: A NEW BROAD-
SPECTRUM ANTIBIOTIC


Shawn Anderson, Pharm.D. Candidate




The emergence of resistant bacteria to a vari-
ety of antibiotics is a major concern to healthcare. In
1995, the Center for Disease Control and Prevention
(CDC), recognizing the importance of such resis-
tance, created a national campaign to reduce antibi-
otic resistance through promotion of appropriate an-
tibiotic use.1 Appropriate antibiotic use consists of
proper prescribing, targeting therapy toward specific
pathogens, and utilizing suitable antibiotic regimens
for an appropriate duration. Simply stated, antibiotic
use contributes to resistance, but widespread misuse
breads resistance.
The antibiotic era is threatened by high levels
of resistance among key pathogens, inadequate sup-
plies of novel antibiotics, and reduction in the num-
ber of drug companies engaged in antibiotic devel-
opment.2 Fifty percent of pneumococcal strains in
the US express resistance to penicillin, 50% of all
Staphylococcus aureus are methicillin resistant
(MRSA), 30% of enterococci are vancomycin resis-
tant (VRE), and 20% of Pseudomonas aeruginosa
are resistant to fluoroquinolones.2 Exacerbating the
problem, in 2002, of 89 new drugs approved, not one
was an antibiotic.3 As of July 2004, only 5 antibiot-
ics were in development, compared to over 500 total
agents in the pipeline. Agents approved in recent
years have major limitations. For example, dapto-
mycin only covers gram-positive organisms and a
few anaerobes, while the broad-spectrum antibiotic,
ertapenem, is inactive against MRSA and less active
than other carbapenems against P. aeruginosa.
Tigecycline, or TygacilTM, is a broad-
spectrum glycylcycline antibiotic that has activity
against gram-positive, gram-negative, anaerobic, and
atypical bacteria.4 Its activity encompasses resistant
pathogens as well. Tigecycline, a structural analog
to tetracycline, overpowers the two types of resis-
tance mechanisms that engender resistance to tetra-
cycline: drug efflux and ribosomal modifications.5


Tigecycline is marketed by Wyeth, and is approved
for the treatment of complicated intra-abdominal
infections (clAI) and complicated skin and skin
structure infections (cSSSI).14 This article will
summarize the pharmacokinetic, safety, and in vitro
data, and examine clinical trials of tigecycline.

Pharmacology and Pharmacokinetics
Tigecycline's mechanism of action is simi-
lar to that of macrolides and aminoglycosides. It
invades bacteria though passive or active pathways
and reversibly binds to the 30S subunit of the ribo-
some. This blocks the entry of transfer RNA into
the A site, which prevents protein synthesis and
bacterial growth.5 Tigecycline is considered bacte-
riostatic.14
Pharmacokinetic data were evaluated in
three groups of men 18- to 50-years-old.6 The 3
groups contained 8 subjects each; 6 received tige-
cycline and 2 received placebo. The first group re-
ceived ascending single intravenous (IV) doses of
tigecycline, from 12.5 mg to 300 mg, infused over
1 or 4 hours. Half of this group received tigecy-
cline in the fed state, while the others received the
antibiotic in the fasting state. The second group
received 25, 50, 75 and 100 mg doses oftigecycline
as 1 hour infusions, every 12 hours for 9 days. The
last group received a 100 mg loading dose, fol-
lowed by 9 doses of 50 mg of tigecycline every 12
hours for 5 days. Results from this study concluded
that tigecycline's serum concentration did not differ
in the fed or fasting state. Dose-proportional Cmax,
or the peak serum concentration, values ranged
from 0.11 to 2.8 [tg/ml and the corresponding
AUCs, or the amount of drug in the body over time,
were 0.75 to 17.8 [tgh/ml. Mean clearance (CL)
was not significantly different among doses, rang-
ing from 0.2 0.3 L/h/kg. The mean half-life was
40 to 60 hours and the mean Vd was larger than 8
L/kg. Vd relates the amount of drug in the body to
the plasma concentration. Tigecycline's large Vd
indicates extensive tissue distribution with steady-
state levels occurring in 7 days. Tigecycline is ex-
creted in bile, but approximately 15% of tigecy-
cline is excreted as unchanged drug. No major me-
tabolites of tigecycline have been identified. Pooled
pharmacokinetic parameters from the tigecycline's
prescribing information are shown in Table 1.
Cmax and AUC were slightly higher in pa-
tients with renal impairment (CrCl < 30 ml/min)







Table 1. Pharmacokinetic Parameters of Tigecycline.14
Single Dose, Multiple Dose,a
100 mg 50 mg ql2h
(N=224) (N=103)
Cmax (tg/mL)b 1.45 0.87
Cmax ([tg/mL) 0.90 0.63
AUC (tg-h/mL) 5.19
AUCO-24h (tg-h/mL) -- 4.70
Cmin (tg/mL) -- 0.13
t% (h) 27.1 42.4
CL (L/h) 21.8 23.8
CLr (mL/min) 38.0 51.0
Vss (L) 568 639
a100 mg initially, followed by 50 mg every 12 hours. b 30-minute infusion, c 60-
minute infusion. Cmax= maximum serum concentration. Cmin= minimum
serum concentration. AUC= area under the concentration-time curve which
represents total drug exposure. t/2 = half-life. CL= clearance. CLr= renal clear-
ance. Vss= volume of distribution at steady state.


and patients with end-stage renal disease on hemodi-
alysis.7 Tigecycline is not significantly removed by
hemodialysis and dosage adjustments for renal im-
pairment are not necessary at this time. No dosage
adjustment is recommended in patients with mild to
moderate hepatic impairment, but in patients with
severe hepatic impairment, the maintenance dose of
tigecycline should be decreased 50% to 25 mg every
12 hours.14
Tigecycline was evaluated in patients of dif-
fering age, race, and gender. Although women and
men aged > 75 years had the highest AUC values, all
pharmacokinetic parameters studied were not signifi-
cantly different.
In vitro studies indicate that tigecycline dem-
onstrates a post-antibiotic effect (PAE). After a sin-
gle dose of tigecycline, the PAE was 8.9 hours for
Streptococcus pneumonia and 4.9 hours for E. coli.8
Such data suggests the potential for tigecycline to
exert an antibacterial effect at sub-MIC concentra-
tions.

Resistance
The primary mechanisms of tetracycline re-
sistance, and possibly tigecycline resistance, involve
ribosomal modification and an active efflux. Tigecy-
cline's higher binding affinity to ribosomes and its
ability to go unrecognized by efflux pumps, allows
tigecycline to overcome resistance at this time.4 Al-
though attempts have been made to induce resistance
in laboratory settings, no resistant isolates have been
observed.9 Therefore, clinically relevant resistant
strains are not expected to develop quickly, though


longitudinal surveillance will be necessary to con-
firm this assumption.5

Spectrum of Activity
Tigecycline has in vitro activity against
gram-positive, gram-negative, anaerobic and atypical
organisms, including resistant strains. Table 2 identi-
fies minimum concentrations (MIC) required to in-
hibit 50% and 90% of isolates (MIC50 and MIC90)
along with MIC ranges. Early breakpoints for sus-
ceptibility to tigecycline are as follows: isolates with
MICs < 2 ug/ml are considered susceptible, and iso-
lates with MICs > 8 ug/ml are considered resistant.4
Tigecycline is active against most gram-
positive aerobes, including methicillin-susceptible S.
aureus (MSSA), methicillin-resistant S. aureus
(MRSA), penicillin-resistant S. pneumoniae (PRSP),
E. faecalis and E. faecium.5 Gram-negative coverage
includes E. coli, Haemophilus influenza, Klebsiella
pneumoniae, Moraxella catarrhalis, Neisseria, Sal-
monella, and .\l/gell// Atypical coverage includes
Mycoplasma pneumoniae and Chlamydia pneumo-
niae; no activity is noted against Mycobacterium
avium. Tigecycline has no activity against Proteus
mirabilis or Pseudomonas aeruginosa.4 Even
though in vitro data provides valuable information,
evaluation of tigecycline in the clinical setting is im-
perative in defining its role in therapy.
To date, only two phase II clinical trials have
evaluated tigecycline in active infections. Postier et
al. compared two doses of tigecycline in cSSSI.10 A
total of 160 patients were randomized to receive tige-
cycline 25 or 50 mg IV doses, every 12 hours for 7 to
14 days. The primary outcome was the clinically
observed cure rate among clinically valuable (CE)
patients at the test-of-cure visit, within 3 weeks of
initiation of therapy. Secondary endpoints were the
clinical cure rate at the end of treatment and bacterial
response in the microbiologically valuable (ME)
patients. Organisms cultured to determine bacterial
response were MRSA, MSSA, S. pyogenes, E. coli,
E. faecalis, and E. faecium. CE patients were re-
quired to receive 7 to 14 days of therapy, complete a
test-of-cure visit, and not receive concomitant antibi-
otics. In 109 CE patients, clinical cure rates were
74% for the 50 mg tigecycline dose and 67% for the
25 mg dose. Bacteriologic response was 70% and
56%, respectively (Table 3).
Murray et al.1 evaluated tigecycline in pa-
tients with complicated intra-abdominal infections.








Table 2. In vitro activity of tigecycline against clinical iso-
lates obtained from 1997-2004.5

MIC (mg/L)


Iso-
lates
Organisms (#)

Gram-positive aerobic pathogens

Staphylococcus aureus

Methicillin-susceptible 160


Methicillin-resistant 170


Community-acquired 10
methicillin-resistant

Glycopeptide- 19
intermediate

Staphylococcus epidermidis

Methicillin-susceptible 159


Methicillin-resistant 155

Streptococcus pneumoniae

Penicillin-susceptible 176


Penicillin-intermediate 305


Penicillin-resistant 270


Enterococcus faecalis



Vancomycin-
susceptible

Vancomycin-resistant


Enterococcus faecium


Vancomycin-
susceptible

Vancomycin-resistant


Range 50% 90%


0.03-
0.25

0.03-2


0.12-
0.25


0.06-1




0.03-2


0.03-1




<0.03-
0.12

<0.03-
0.03

<0.03-
0.25


0.03-
0.25

<0.016
-0.5




<0.03-
0.25

<0.03-
0.25


0.12


0.12


0.12


0.25


0.12 0.25



0.12 0.25


0.12


0.12




<0.03


<0.03


<0.03


0.06


0.06






0.06


<0.03


0.5


0.5




0.06


0.06


0.06


0.12


0.12






0.12


0.12


Acinetobacter baumannii


Anaerobes

Bacteroides fragilis

Prevotella spp.

Clostridium difficile


Clostridium perfringens


Peptostreptococcus spp.


Table 2 Continued.

Gram-negative aerobic pathogens

Citrobacter freundii 160


Enterobacter aerogenes 161


Enterobacter cloacae 160


Escherichia coli


Non-ESBL producing 208


ESBL producing 170

Klebsiella pneumoniae

Non-ESBL 180

ESBL producing 171

AmpC producing 89

Proteus mirabilis 160


Serratia marcescens 160


Salmonella enterica ser 229
Enteritidis


h .. I//,, sonnei 274


Pseudomonas aeruginosa 160


0.25


0.25


0.25-8 0.5 0.5


0.06-


0.06-


0.25-4

0.12-4

0.25-4

0.5-16


0.25-8


0.12


0.25




0.5

0.5

1

4


1


0.12-2 0.5 1


0.06-1 0.25 0.5


0.25-32


158 0.03-4


0.015-32

0.015-1

<0.06-0.5


0.03-4


0.015-
0.25


8 16



0.5 2


1

0.12

0.25


0.06


0.06


<0.06-8


<0.06-4







Table 3. Results from clinical trials with tigecycline.
Indi- Patients Clinical Cure Microbiological Clinical cure Microbiological
Study cation (#) Dose Rate TOC cure rate at TOC rate EOT cure at EOT
Postieret al1 cSSTI 160 25 mg 67% 56% 78% 62%
Postieret al. cSSTI 160
50 mg 74% 69% 85% 74%
Murray et AI 111 LD 66.7% 66.7% 75.8% 75.8%
al. 50 mg q12h

300 and 30514 cSSTI 422 100 mgLD, 86.5% 79.7% NA NA
50 mg ql2h
301 and 30614 clAI 512 100 mgLD 86.1% 80.2% NA NA
50 mg ql2h
cSSTI = complicated skin and soft tissue infections; clAI= intra-abdominal infections; TOC = test of cure; EOT = end of treatment; LD = loading dose; NA = not
available.


Sixty-six patients met the inclusion criteria and had a
diagnosis of perforated gangrenous appendicitis,
complicated cholecystitis, perforated diverticulitis, or
peritonitis and a follow-up visit. All patients re-
ceived a 100 mg IV tigecycline loading dose, fol-
lowed by 50 mg IV every 12 hours for 5 to 14 days.
Clinical cure rates at the test-of-cure and end-of-
treatment visits were 67% and 76%, respectively
(Table 3).
Prescribing information for tigecycline high-
lights two phase III clinical trials for the treatment of
cSSSI and two phase III clinical trials for the treat-
ment of clAI. Results from these trials are also sum-
marized in Table 3.

Toxicity and Safety
A complete list of adverse events with tigecy-
cline have recently been published.14 Specific warn-
ings in the prescribing information for tigecycline are
to avoid use in pregnancy, during tooth development,
and any persons with known hypersensitivity to tige-
cycline. Tigecycline, like all antibiotics, has the po-
tential to cause pseudomembranous colitis.14 The
most common adverse events in clinical trials were
nausea, vomiting, and diarrhea. (Table 4) In a study
utilizing tigecycline for complicated skin infections,
both the 25 mg and 50 mg doses were well toler-
ated.10 Most adverse events did not result in dicon-
tinuation of study drug. Six of 160 study patients
(4%) discontinued therapy due to nausea and vomit-
ing (2), diarrhea (1), paresthesia (1) and allergic re-
action (1). Laboratory abnormalities included ele-
vated serum transaminases in 5 patients, elevated
serum alkaline phosphatase in 2 patients, elevated
blood urea nitrogen in one patient and anemia in one
patient. No patient discontinued therapy due to ab-


normal lab results.

Dosing and Administration
In pharmacokinetic studies, tigecycline doses
have range from 12.5 mg to 300 mg daily.612'13 Tige-
cycline is only available as a parenteral infusion. In
clinical trials, tigecycline was administered as a 100
mg IV loading dose, followed by 50 mg IV every 12
hours for 5 to 14 days. According to a pharmacoki-
netic study by Muralidharan,6 the maximum toler-
ated fasting dose of tigecycline was 100 mg and the
maximum non-fasting dose was 200 mg. GI adverse
events increased with increasing tigecycline doses
and doses above 300 mg were poorly tolerated.
Varying the infusion time from 30 minutes to 4 hours
had no effect on adverse events. The approved dose
of tigecycline for patients 18 years and older is an
initial dose of 100 mg, followed by 50 mg every 12
hours. IV infusions of tigecycline should be admin-
istered over 30-60 minutes.14

Cost
Tigecycline is available in packages that con-
tain ten 50 mg vials. The cost for 10 vials is $452.30.
Thus, a course of tigecyline is expected to cost any-
where from $226.15 to $633.22 (5-14 days) depend-
ing on duration. (Personal communication with
Wyeth, September 8, 2005)

Summary
Tigecycline is a broad-spectrum glycylcy-
cline antibiotic approved for the treatment of compli-
cated intra-abdominal infections (clAI) and compli-
cated skin and skin structure infections (cSSSI). It
demonstrates activity against gram-positive, gram-
negative, anaerobic, and atypical bacteria. Tigecy-








Table 4. Adverse events of tigecycline during clinical and pharmacokinetic trials.
Postier et al.11 Muralidharan et al.6

25 mg Tigecycline 50 mg Tigecycline
Adverse event n = 79 n = 81 12.5 300mg Tigecycline
Nausea 22% 35% 48.5%
Vomiting 13% 19% 29.4%
Diarrhea 11% 9% NR
Pulmonary physical finding 11% 4% NR
Headache 8% 5% NR
Pain 6% 6% NR
Fever 5% 6% NR
Insomnia 5% 6% NR
Dizziness 5% 3% NR
Hypertension 5% 3% NR
Anemia 5% 1% NR


cline's activity includes resistant organisms, such as
MRSA, PRSP, and VRE, while possessing a low po-
tential for inducing resistance. Pharmacokinetic data
suggests significant distribution of tigecycline into
tissues, which increases the drug concentration at the
site of infection and allows for a shorter duration of
therapy. Tigecycline possesses a long half-life. This
characteristic allows for convenient dosing and
maintains tigecycline's serum concentration above
the MIC for longer time intervals. Nausea and vom-
iting are the most common adverse events of tigecy-
cline, but can be reduced at dosages of 100 mg or
less on a full stomach. Current and future clinical
trials, with larger numbers of patients, should help
define tigecycline's role in therapy.

References:
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June 2005. www.fda.gov/cder/drug/antimicrobial/
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4. Garrison MW, Neumiller JJ, Setter SM. Tigecycline An
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12. Muralidharan G, Fruncillo RJ, Micalizzi M, Raible DG,
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