N E W S & A N A LY S I S

FRESH FROM THE PIPELINE

Tigecycline
Richard Wenzel, Guy Bate and Peter Kirkpatrick

Tigecycline

Tigecycline (Tygacil;Wyeth) was approved

by the US FDA for the treatment of a range
of bacterial infections in June 2005. It is the
first in a new generation of tetracyclines
known as glycylcyclines, which have been
developed to overcome the problems of
resistance to earlier tetracyclines.

50 mg every 12 hours) was compared with

vancomycin (1 g intravenously every 12
hours)/aztreonam (2 g intravenously every
12 hours) for 514 days. The primary efficacy endpoint was the clinical response at
the test of cure (TOC) visit in the co-primary
populations of the clinically evaluable (CE)
and clinical modified intent-to-treat (cmITT)
patients. The clinical cure rates for patients
receiving tigecycline were 86.5% (CE) and
79.7% (cmITT) compared with 88.6% (CE)
and 81.9% (cmITT) for patients receiving
vancomycin/aztreonam5.
Tigecycline was also assessed for the
treatment of complicated intra-abdominal
infections in two randomized, double-blind,
active-controlled studies involving more
than 1,000 adult patients. Tigecycline (100
mg intravenous initial dose followed by
50 mg every 12 hours) was compared with
imipenem/cilastatin (500 mg intravenously
every 6 hours) for 514 days. The primary
efficacy endpoint was the clinical response at
the TOC visit for the co-primary populations
of the microbiologically evaluable (ME) and
the microbiological modified intent-to-treat
(m-mITT) patients. The clinical cure rates
for patients receiving tigecycline were 86.1%
(ME) and 80.2% (m-mITT), compared with
86.2% (ME) and 81.5% (m-mITT) for patients
receiving imipenem/cilastatin5.

There is a pressing need for new antibiotics

to combat the worsening problem of bacterial resistance to existing agents1. Strains of
potentially life-threatening bacteria such as
Staphylococcus aureus, the leading cause of
hospital-acquired infections, that are resistant to multiple antibiotics even those that
have historically been highly reliable, such
as vancomycin are becoming increasingly
widespread1.
The main approach for developing new
antibiotics in the past has been to modify
existing drug classes to restore activity against
bacteria that have become to resistant to the
previous generation of drugs1. But although
the development of second- and third-generation drugs in the major antibacterial classes,
including penicillins, cephalosporins, macrolides and quinolones, have helped keep
antibiotic resistance at bay, success with this
strategy is becoming much harder to achieve.
Furthermore, agents in completely new classes
have been very rare; only two such antibiotics, linezolid (Zyvox; Pfizer) and daptomycin
(Cubicin; Cubist), have been introduced in the
past four decades.

Drug properties

In common with previous tetracyclines, tigecycline inhibits bacterial protein synthesis by

binding to the 30S ribosomal subunit25. It
blocks entry of amino-acyl tRNA molecules
into the A site of the ribosome, preventing
incorporation of amino-acid residues into
elongating peptide chains25.
The two main tetracycline-resistance
mechanisms are ribosomal protection and
active drug efflux2. Tigecycline is not affected
by either of these mechanisms, which is
thought to be because of steric hindrance due
to the large 9-t-butyl-glycylamido side chain
(FIG. 1)25. It has been shown to have in vitro and
in vivo activity (generally bacteriostatic) against
a broad spectrum of bacterial pathogens, and
no cross-resistance with other antibiotics has
been observed25, providing a strong rationale
for its clinical evaluation.
Clinical data

The potential of tigecycline for the treatment of complicated skin and skin-structure
infections was evaluated in two randomized,
double-blind, active-controlled studies
involving more than 800 adults. Tigecycline
(100 mg intravenous initial dose followed by

H3C

H3C

CH3

Indications

H
OH

O
N
H
NH

NH2
OH
OH

OH

Tigecycline
4S,4aS,5aR,12aS)-9-[2-(tert-butylamino)acetamido]
-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,
12a-octahydro-3,10,12,12a-tetrahydroxy1,11-dioxo-2-naphthacenecarboxamide;
C29H39N5O8; Mr = 585.65;
CAS number: 220620-09-7

Figure 1 | Tigecycline. In the 1990s, it was

discovered that introducing substituents at
position 9 of minocycline resulted in compounds
that not only had activity typical of earlier
tetracyclines, but also displayed activity against
bacteria containing resistant genes responsible for
efflux of earlier tetracyclines (tetAtetD and tetK)
and ribosomal protection (tetM)2. The 9-t-butylglycylamido derivative of minocycline GAR-936,
later known as tigecycline was selected as a
clinical candidate.

Tigecycline is approved for the treatment of

infections caused by susceptible strains of
the designated microorganisms in the conditions listed below for patients 18 years of age
and older: complicated skin and skin-structure infections caused by Escherichia coli,
Enterococcus faecalis (vancomycin-susceptible
isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates),
Streptococcus agalactiae, Streptococcus anginosus grp, Streptococcus pyogenes and Bacteroides
fragilis; and complicated intra-abdominal
infections caused by Citrobacter freundii,
Enterobacter cloacae, E. coli, Klebsiella oxytoca,
Klebsiella pneumoniae, E. faecalis (vancomycinsusceptible isolates only), S. aureus (methicillinsusceptible isolates only), S. anginosus grp,
B. fragilis, B. thetaiotaomicron, B. uniformis,
B. vulgatus, Clostridium perfringens and
Peptostreptococcus micros5.

NATURE REVIEWS | DRUG DISCOVERY

CH3
H

Basis of discovery

The first tetracycline antibiotics were discovered more than 50 years ago, and represented
a significant advance in the treatment of many
Gram-positive and Gram-negative bacterial
infections. However, following their initial
widespread use, a high incidence of tetracycline resistance among many bacteria has led
to tetracyclines being relegated to second- or
third-line therapy.
In an attempt to restore the potential of
tetracyclines as broad-spectrum antibiotics,
systematic searches for tetracycline analogues
with activity against both tetracycline-susceptible and tetracycline-resistant organisms were
performed in the early 1990s2. These efforts
led to the identification of the glycylcyclines,
including tigecycline24 (FIG. 1).

VOLUME 4 | O CTOBER 2005 | 809

N E W S & A N A LY S I S

ANALYSIS | ANTIBACTERIALS

Analysing clinical issues in the treatment

of bacterial infections is Richard Wenzel,
M.D., M.Sc., Professor and Chairman of
the Department of Internal Medicine at
the Medical College of Virginia Campus,
Virginia Commonwealth University,
Richmond, Virginia, USA.
What are the current major needs in antibacterial therapy?
Of patients entering hospitals in developed
countries, 510% acquire a nosocomial infection, 10% of which involve the bloodstream
(350,000700,000 septicemias annually in the
United States). The leading causes of nosocomial
bloodstream infections (BSIs) are coagulase-negative staphylococci, S. aureus and enterococci,
and their respective crude mortality rates are
21%, 25%, and 34%6. In the United States, it has
been estimated that the mortality from nosocomial BSIs is equivalent to the eighth leading cause
of death7. Among the bloodstream isolates, 75%
of coagulase-negative staphylococci and 41% of
S. aureus are resistant to methicillin; 60% of E.
faecium isolates are resistant to vancomycin6.
Importantly, intensive care unit patients with
BSIs who are not treated in the first 24 hours with
antibiotics active against the offending pathogen

have twice the crude mortality of those appropriately treated (62% vs. 32%)8. So, new agents
active against common, life-threatening healthcare-associated infections are much needed.
In the community, pneumococcus causes
1020% of pneumonias but half of all pneumonia-related deaths. Recently, a review of
invasive S. pneumoniae isolates in the United
States reported 34% resistance to penicillin,
2829% for all macrolides, 7% to ceftriaxone
and 2% to fluoroquinolones9. Thus, there is
also a pressing need for effective drugs to treat
serious community-associated infections.
How well do emerging therapies such as tigecycline address these needs?
Tigecycline is highly active in vitro against both
nosocomial and community-acquired methicillin-susceptible or -resistant S. aureus strains,
vancomycin-susceptible or -resistant E. faecium
and E. faecalis, and penicillin-susceptible or resistant strains of S. pneumoniae10. Tigecycline
therefore has great promise as a new therapeutic
agent against important pathogens.
In clinical trials involving patients with skin
and soft-tissue infections, tigecycline showed
equivalence but not superiority compared with
vancomycin/aztreonam11. So, advantages of
tigecycline would include its relative safety (no

reports of end organ failure) for treating methicillin-resistant S. aureus. However, nausea and
vomiting did occur more often with tigecycline
(35% and 20%, respectively) than with vancomycin/aztreonam (8% and 4%, respectively). Its
advantages compared with linezolid or daptomycin for methicillin-resistant S. aureus await
direct clinical comparisons. For vancomycinresistant enterococci, tigecycline might find a
particularly useful niche because of its safety,
but clinical studies are needed. These are also no
trial data comparing tigecycline with available
agents for invasive pneumococcal infections.
The advantages of tigecycline for complicated
intrabdominal infections are less clear. It was
equivalent to imipenem in comparative studies12,
and both imipenem and piperacillin/tazobactam
have excellent track records. Furthermore,
both have activity against Proteus mirabilis
and Pseudomonas aeruguinosa (an uncommon
intrabdominal pathogen) not noted with tigecycline. Nevertheless, a potential advantage for
tigecycline would be as an alternative for patients
with serious allergies to -lactam antibiotics.
Richard Wenzel is at the Department of Internal
Medicine, Virginia Commonwealth University,
Richmond, Virginia, USA. Guy Bate is at IMS
Health, 7 Harewood Avenue, London NW1 6JB, UK.
Peter Kirkpatrick is at Nature Reviews Drug
Discovery, UK. e-mails: rwenzel@mcvh-vcu.edu;
gbate@uk.imshealth.com; p.kirkpatrick@nature.com

Box 1 | Market analysis

doi:10.1038/nrd1857

Analysing the market for intravenous antibiotics is Guy Bate, Ph.D., Principal, Product and
Portfolio Development, IMS Consulting & Services, IMS Health, London, UK.

1.

Intravenous antibiotics market. Across the key pharmaceutical markets of the US, the top
five European countries (France, Germany, Italy, UK and Spain) and Japan, the market for
intravenous (IV) antibiotics was worth ~US$7 billion (34% of all antibiotics sales) in 2004 but
grew at just under 5% over 200313. Despite this lacklustre performance, the IV segment is outperforming the overall antibiotics market, which is shrinking (sales fell 4.5% in 2004).
The United States is the largest market for IV antibiotics, representing more than 40% of the
overall market, with sales of ~US$3 billion in 200413. Europe and Japan contribute ~US$2.4 billion
(33% of sales across the key markets) and ~US$1.7 billion (23%), respectively13.
In terms of chemical class, cephalosporins have had the highest sales at US$2.6 billion,
contributing nearly 40% of the overall IV antibiotic sales value in our key markets13. However,
the use of cephalosporins is waning. The market value of this class shrank by 4% in 2004 and 90%
of the top products have growth running flat to negative. The next largest selling classes are the
broad-spectrum penicillins (16% of total IV antibiotic sales in key markets), carbapenems (13%),
fluoroquinolones (10%) and glycopeptides (8%), based on 2004 sales value.
Tigecycline. Tigecycline is a first-in-class glycylcycline IV antibiotic for the treatment of complicated
intra-abdominal and complicated skin and skin-structure infections in adults. Tigecyclines
structure is similar to that of the tetracyclines but additional structural elements increase its
potency and impede the mechanisms of bacterial resistance associated with the tetracyclines.
The resistance profile will be the real key to tigecyclines market value, which analysts
high-end estimates suggest could reach a peak of US$600700 million per year once further
indications, such as community- and hospital-acquired pneumonia, have been added to the
label. A highly attractive tolerability profile, with no observed effect on kidney or liver function,
plus a relatively convenient twice-daily dosing regimen that needs no adjustment in patients
with impaired renal function, are also notable positives for the products market potential.

810 | O CTOBER 2005

| VOLUME 4

2.
3.

4.

5.
6.

7.

8.

9.

10.
11.

12.

13.

Walsh, C. Where will new antibiotics come from? Nature.

Rev. Microbiol. 1, 6569 (2003).
Chopra, I. Glycylcyclines: third-generation tetracycline
antibiotics. Curr. Opin. Pharmacol. 1, 464469 (2001).
Sum, P. E. & Petersen, P. Synthesis and structureactivity
relationship of novel glycylcycline derivatives leading to the
discovery of GAR-936. Bioorg. Med. Chem. Lett. 9, 1459
1462 (1999).
Petersen, P. J. et al. In vitro and in vivo antibacterial activities
of a novel glycylcycline, the 9-t-butylglycylamido derivative
of minocycline (GAR-936). Antimicrob. Agents Chemother.
43, 738744 (1999).
FDA labelling information [online], <http://www.fda.gov/
cder/foi/label/2005/021821lbl.pdf> (2005).
Wisplinghoff, H. et al. Nosocomial bloodstream infections in
US hospitals: analysis of 24,179 cases from a prospective
nationwide surveillance study. Clin. Infect. Dis. 39, 309317
(2004).
Wenzel, R. P. & Edmond, M. B. The impact of hospitalacquired bloodstream infections. Emerging Infect. Dis. 7,
174177 (2001).
Ibrahim, E. H. et al. The influence of inadequate antimicrobial
treatment of bloodstream infections on patient outcomes in
the ICU setting. Chest 118, 146155 (2000).
Doern, G. V. et al. Antimicrobial resistance among
Streptococcus pneumoniae in the United States: Have we
begun to turn the corner on resistance to certain
antimicrobial classes? Clin. Infect. Dis. 41, 139148 (2005).
Noskin, G. A. Tigecycline: a new glycylcycline for treatment
of serious infections. Clin. Infect. Dis. 41, s303s314 (2005).
Ellis-Grosse, E. J. et al. The efficacy and safety of tigecycline
in the treatment of skin and skin-structure infections: results
of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin. Infect. Dis. 41, s341353 (2005).
Babinchak, T. et al. The efficacy and safety of tigecycline for
the treatment of complicated intra-abdominal infections:
analysis of pooled clinical trial data. Clin. Infect. Dis. 41,
s354-s367 (2005).
IMS Health analysis, IMS MIDAS Quantum, MAT (Dec 2004).

www.nature.com/reviews/drugdisc