Tigecycline

Standard Slide
Deck
PP-TYG-IDN-0018-NOV-2021

PT. Pfizer Indonesia

28th Floor, World Trade Center 3
Jl. Jend. Sudirman Kav 29-31
Jakarta 12920, Indonesia 1
Disclaimer

• The content in this presentation is only intended for Healthcare Professionals in Indonesia.
• The views and opinions mentioned in the presentation is strictly that of the author and the individuals
expressing the same and Pfizer may not necessarily endorse the same. Pfizer (including its parent, subsidiary
and affiliate entities). Makes no representation or warranties of any kind, expressed or implied; as to the
content used in the presentation and/or the accuracy, completeness of its content.
• Pfizer advocates the use of its medication as approved by the local regulatory governance which can be
found in the prescribing information.
• Physicians have the professional responsibility to ensure that pharmaceutical products are prescribed and
used appropriately, based on their own judgement and accepted standards of care.
 • Therapy area overview
• Tigecycline molecule

• Indications and dosing

CONTENTS • Clinical data
• Safety and tolerability

• Key take-aways

3
Complicated skin and soft-tissue infections

• cSSTIs are the most severe SSTIs. Examples of cSSTIs include:1

– Infective cellulitis, ulcer or wound-site infections, infected burns,
Diabetes
surgical-site infections, major abscesses, and skin and diabetic foot
ulcers Antibiotic
use in past Age
• SSTIs often require hospitalisation and are regarded as 30 days
‘complicated’ once the infection penetrates to the deeper
subcutaneous tissue and/or when surgery is required 2 Risk
• cSSTIs are reported to account for up to 10% of admissions factors2,
Hospitalisatio 4

to infection units in the US and in the UK3 n in past

6 months
Race

– In a retrospective US study, the rate of clinically diagnosed SSTIs was

496 per 10,000 person-years4
Peripheral
• cSSTIs are a common cause of morbidity and mortality2 vascular Ethnicity
– Mortality rates in hospitalised cSSTI patients in studies range from disease
0.4% to 26.7%​
Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

1. Leong HN, et al. Infect Drug Resist. 2018;11:1959–74; 2. Bassetti M, et al. Clin Microbiol Infect.

2014;20(Suppl. 4):3–18; 3. Garau J, et al. Clin Microbiol Infect. 2013;19:E377–85;
cSSTI, complicated skin and soft-tissue infection; SSTI, skin and soft-tissue infection 4. Ray GT, et al. BMC Infect Dis. 2013;13:252.​ 4
 cSSTI epidemiology

• cSSTIs can be monomicrobial, where infection is caused by a single species of Gram-positive ​or

Gram-negative bacteria, or polymicrobial, caused by multiple species, with increased systemic inflammatory
responses1,2
• Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Enterococcus spp., Enterobacter spp., Klebsiella
spp. and β-Streptococcus are the most frequently encountered pathogens causing SSTIs in hospitalised patients 2
– The most common causative agent of cSSTIs is S. aureus1

• A rise in antibiotic-resistant microorganisms, particularly multidrug-resistant organisms, has complicated

KEY POINTS

the treatment of cSSTI

• Management of polymicrobial or mixed infections requires a multidrug approach that is effective against aerobic,
anaerobic and facultative bacteria
• The rapid emergence of MRSA infections, endemic to several countries worldwide, has confounded the treatment
of cSSTIs and increased cSSTI burden worldwide2
Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

1. Garau J, et al. Clin Microbiol Infect. 2013;19:E377–85;
MRSA, methicillin-resistant S. aureus 2. Leong HN, et al. Infect Drug Resist. 2018;11:1959–74.​ 5
cSSTI guidelines

• Most international guidelines recommend initial management with empirical antibiotic therapy against
locally prevalent MRSA strains1
• The IDSA and NICE recommend bacterial culture assessment to aid the selection of antibiotics against the
causative pathogens and initiate definitive therapy for severe infection, non-responsiveness to the current
line of antibiotics or recurrent infections2,3
Recommendations for antibiotic treatment of MRSA cSSTI1
Guidelines Infection Recommended therapy
IDSA cSSTI (deeper soft-tissue infections, surgical/traumatic-wound infection, • Surgical debridement
major abscesses, cellulitis, and infected ulcers and burns) • Vancomycin, linezolid, daptomycin, telavancin, clindamycin
Non-purulent cellulitis • β-lactam antibiotic active against MRSA
Surgical Infection Society Complex abscesses with cellulitis and polymicrobial cSSTIs • Incision and drainage (in case of abscess)
• Vancomycin, clindamycin, linezolid or erythromycin
Gruppo Italiano di Studio sulle Infezioni Gravi MRSA-related cSSTIs and severe surgical infections • Use of TNP/VAC (for deep surgical infections)
• Vancomycin, teicoplanin, linezolid, tigecycline, daptomycin
Italian Society of Infectious Diseases and MRSA-related cSSTIs • Early surgical treatment wherever feasible
International Society of Chemotherapy • Vancomycin, teicoplanin, linezolid, tigecycline, daptomycin
Spanish Society of Chemotherapy MRSA-related cSSTIs • Linezolid, daptomycin, vancomycin, teicoplanin
British Society of Antimicrobial Severe cSSTI with MRSA • Linezolid, daptomycin, vancomycin, teicoplanin
Chemotherapy

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

IDSA, Infectious Diseases Society of America; 1. Leong HN, et al. Infect Drug Resist. 2018;11:1959–74; 2. Stevens DL, et al. Clin Infect Dis.
NICE, National Institute for Health and Clinical Excellence; 2014;59(2):e10–e52; 3. NICE Surgical site infection prevention and treatment of surgical site infection. 2013.
TNP, topical negative pressure; VAC, vacuum-assisted closure https://www.nice.org.uk/guidance/qs49/resources/surgical-site-infection-2098675107781 [Last accessed August 2019]. 6
Complicated intra-abdominal infections
• cIAIs are infections of the peritoneal space that are associated
with either peritonitis or abscess formation1
– Peritonitis is further categorised as primary, secondary or tertiary 2 Extent of
disease
– These can be community-acquired (~70% of all secondary
Poor
peritonitis) or post-operative (~30%), which are usually nutritional Age
status
polymicrobial infections and have an increasing likelihood
of being due to antimicrobial-resistant strains 2
– cIAIs are commonly defined as ‘complicated’ by the SIS Risk
and IDSA guidelines3 factors5
Inadequate Physiological
• cIAI are a common cause of morbidity and mortality, particularly debridement severity

in surgical patients1
– Inadequate infection source control and inappropriate antibiotics
are key determinants of mortality in patients having intra-abdominal Delay in
Comorbidities
intervention
sepsis and associated bacteraemia4

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

1. Leone S, et al. Eur J Clin Microbiol Infect Dis. 2019;38(5):819–27; 2. Eckmann C, et al.
J Antimicrob Chemother. 2013;68(Suppl. 2):ii25–35; 3. Solomkin JS, et al. Surg Infect (Larchmt). 2010;11:79–109;
cIAI, complicated intra-abdominal infection; SIS, Surgical Infection Society 4. Sartelli M, et al. World J Emerg Surg. 2017;12:22; 5. Solomkin J, et al. Surg Infect (Larchmt). 2016;17(4):402–11. 7
cIAI epidemiology

• Local epidemiology is variable, but some of the most commonly isolated pathogens in cIAIs are:
Gram-negative Enterobacter spp., E. coli, Klebsiella spp., Proteus spp., P. aeruginosa and the Gram-positive Enterococcus spp.,
Staphylococcus spp. and Streptococcus spp.1
• Failure to initiate early appropriate antimicrobial therapy can lead to an increased risk of clinical
failure and increased healthcare costs1
– Inappropriate antimicrobial therapy may delay clinical resolution and increase hospital LOS and the risk of mortality 2
KEY POINTS

• Knowledge of local epidemiology is key in identification of the causative agent of cIAI

• The epidemiological shift towards drug-resistant pathogens in cIAIs, together with the limited number
of currently available appropriate antimicrobial agents, presents a challenge for the successful management
of this infection, especially in the population of severely ill, high-risk patients 1

Tigecycine should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

1. Eckmann C, et al. J Antimicrob Chemother. 2013;68(Suppl. 2):ii25–35;

LOS, length of stay 2. Babinchak T, et al. Clin Infect Dis. 2005;41(Suppl. 5):S354–67. 8
cIAI guidelines

• World Society of Emergency Surgery (WSES) 2016 guidelines1

– Empirical antimicrobial therapy should be based on local epidemiology, individual patient risk factors
for difficult-to-treat pathogens, clinical severity of infection and infection source (Recommendation 1C)
– Broad empiric antimicrobial therapy should be started as soon as possible in patients with organ dysfunction (sepsis)
and septic shock
– For patients with CA-IAIs, agents with a narrower spectrum of activity should be suggested. However, according to
local ecology, anti-ESBL-producer coverage may be warranted. By contrast, for patients with HA-IAIs, antimicrobial
regimens with broader spectra of activity are preferred (Recommendation 1B)
– Carbapenem-sparing treatment should be recommended particularly in settings where there is a high incidence of
carbapenem-resistant K. pneumoniae (Recommendation 1B)
• In addition, the SIS and IDSA 2010 evidence-based guidelines have specific recommendations for
empirical antimicrobial therapy choice in specific subsets of patients with IAI2
Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

CA-IAI, community-acquired intra-abdominal infection; 1. Sartelli M, et al. World J Emerg Surg. 2017;12:22;
ESBL, extended-spectrum β-lactamase; HA-IAI, hospital-acquired intra-abdominal infection 2. Solomkin JS, et al. Surg Infect (Larchmt) 2010;11:79–109. 9
Pharmacodynamics and pharmacokinetics

• Intravenous, broad-spectrum glycylcycline antibiotic1

– Inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of aminoacyl-tRNA molecules into the A site of the
ribosome
– Tigecycline binds five times more efficiently to this ribosomal site compared with the tetracyclines2
• In general, Tigecycline is considered bacteriostatic1
– At four times the MIC, a 2-log reduction in colony counts was observed with Tigecycline against Enterococcus spp., S. aureus and E. coli
• MIC breakpoints established by EUCAST are as follows:1
Susceptible Resistant
Staphylococcus spp. ≤0.5 mg/L >0.5 mg/L
Streptococcus spp. other than S. pneumoniae ≤0.25 mg/L >0.5 mg/L
Enterococcus spp. ≤0.25 mg/L >0.5 mg/L
Enterobacteriaceae (E. coli and Citrobacter koseri) ≤1 mg/La >2 mg/Lb

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents
Tigecycline has decreased in vitro activity against Proteus, Providencia and Morganella spp.
a 1. Latest BPOM Approved [TYGACIL] Local Product Document_[2021]; 2. Bergeron J, et al. Antimicrob
b
Please refer to EUCAST guidance document3 for further information on K. pneumoniae. Agents Chemother. 1996;40:2226–8. 3. EUCAST, Guidance Document on Tigecycline Dosing. December
A, aminoacyl; EUCAST, European Committee on Antimicrobial Susceptibility Testing; 2018. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/General_documents/
MIC, minimum inhibitory concentration; tRNA, transfer ribonucleic acid Tigecycline_Guidance_document_20181223.pdf [Last accessed August 2019]. 10
Activity and resistance profile

• Broad spectrum of activity, including Gram-positives, Gram-negatives and anaerobes 1

– Tigecycline is approved for treatment of cIAI due to resistant Gram-positive bacteria (MRSA) 2

Gram-positive aerobes Gram-negative aerobes Anaerobes1

Enterococcus spp. Citrobacter freundii Clostridium perfringens
Staphylococcus aureus Citrobacter koseri Peptostreptococcus spp.
Staphylococcus epidermidis Escherichia coli Prevotella spp.
Staphylococcus haemolyticus Klebsiella oxytoca
Streptococcus agalactiae
Streptococcus anginosus group (includes
S. anginosus, S. intermedius and S. constellatus)
Streptococcus pyogenes
Viridans group streptococci

• Resistance1
– Tigecycline is able to overcome the two major tetracycline resistance mechanisms, ribosomal protection and efflux
– Cross-resistance between Tigecycline and minocycline-resistant isolates among the Enterobacteriaceae due to multidrug resistance efflux pumps has
been shown
– There is no target-based cross-resistance between Tigecycline and most classes of antibiotics
Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

1. Latest BPOM Approved [TYGACIL] Local Product Document_[2021].

VRE, vancomycin-resistant Enterococcus 2. Eckmann C, et al. J Antimicrob Chemother. 2013;68(Suppl. 2):ii25–35. 11
Indications and dosing

• TYGACIL is a tetracycline class antibacterial indicated in patients 18 years of age and older for:
- Complicated skin and skin structure infections
- caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -
resistant isolates), including cases with concurrent bacteremia, Streptococcus agalactiae, Streptococcus anginosus grp. (includes S.anginosus, S.
intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.
• - Complicated intra-abdominal infections
– caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli (includes ESBL producing isolates), Klebsiellaoxytoca, Klebsiella
pneumoniae (includes ESBL producing isolates), Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus
(methicillinsusceptible and -resistant isolates), including cases with concurrent bacteremia, Streptococcus anginosus grp. (includes S. anginosus,
S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus,
Clostridium perfringens, and Peptostreptococcus micros.

Tygacil dosing
Patient subgroup Dosing regimen Duration
Adults 100 mg loading dose, followed by 50 mg every 12 hours 5–14 daysa

Tygacil should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

Latest BPOM Approved [TYGACIL] Local Product

The duration of therapy should be guided by the severity, site of the infection and the patient’s clinical response
a Document_[2021]. 12
Contraindications and special warnings

• Hypersensitivity to the active substance or to any of the excipients (lactose monohydrate, hydrochloric acid, sodium
hydroxide)1
• Patients hypersensitive to tetracycline class antibiotics may be hypersensitive to Tygacil 1
• Special warnings1
– Anaphylaxis/anaphylactoid reactions, potentially life-threatening, have been reported with Tygacil
– Cases of liver injury with a predominantly cholestatic pattern have been reported in patients receiving Tygacil treatment, including some cases of hepatic
failure with a fatal outcome. Although hepatic failure may occur in patients treated with Tygacil due to the underlying conditions or concomitant
medicinal products, a possible contribution of Tygacil should be considered
– Tygacil may have adverse reactions similar to tetracycline-class antibiotics
– Acute pancreatitis, which can be serious, has occurred (frequency: uncommon) in association with Tygacil treatment
– Experience in the use of Tygacil for treatment of infections in patients with severe underlying diseases is limited
• In 2013, the US FDA issued a black box warning of increased risk of mortality of Tygacil versus comparator drugs. However,
Tygacil may likely be considered instead of combination therapy, where this is deemed necessary,
due to its broad-spectrum activity2
Tygacil should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

1. Latest BPOM Approved [TYGACIL] Local Product Document_[2021];

FDA, food and drug administration 2. Leong HN, et al. Infect Drug Resist. 2018;11:1959–74. 13
Global cSSTI study: overview
• Study aim
– To determine the safety and efficacy of Tigecycline versus vancomycin–aztreonam
• Study design
– Two Phase III, randomised, double-blind studies were conducted across a total of 118 centres in 29 countries
for patients with cSSTIs between 2001–2004
• Objectives
– To evaluate clinical response to Tigecycline and vancomycin–aztreonam in hospitalised adults with cSSTIs
 Patients were considered clinically evaluable if they had received at least one dose of study drug, had clinical evidence
of a cSSTI (cMITT population), did not have P. aeruginosa as a sole baseline isolate, received no concomitant antibiotic
after their first dose of study medication and had an assessment of cure or failure at the test-of-cure visit
• Patients were assessed as ‘cure’ if there was resolution of the patient’s signs and symptoms at the test-of-cure visit
• Patients were assessed as ‘failure’ if there was inadequate response to therapy, requiring additional antibiotic therapy
or unplanned surgical intervention
• Patients were evaluated as ‘indeterminate’ if there was no evaluation possible for any reason
Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

cMITT, clinically modified intent-to-treat Ellis-Grosse EJ, et al. Clin Infect Dis. 2005;41(Suppl. 5):S341–53. 14
Global cSSTI study: results
Population, Tigecycline Vancomycin–aztreonam Difference Test for Test for
type of infection (Tigecycline & noninferiority differences
• In the cMITT population, clinical cure No. of Percentage of No. of Percentage of vancomycin–
aztreonam,
p
patients/ patients (95% CI) patients/ patients (95% CI)
was reported for 79.7% of patients total total % (95% CI)

treated with Tigecycline, compared

to 81.9% of patients treated with Clinically evaluable 365/422 86.5 (82.9–89.6) 364/411 88.6 (85.1–91.5) –2.1 (–6.8 to 2.7) <0.001 0.4233

vancomycin–aztreonam cMITT 429/538 79.7 (76.1–83.1) 425/519 81.9 (78.3–85.1) –2.1 (–7.1 to 2.8) <0.001 0.4183

• Results were similar for the clinically

Microbiologically
evaluable population, where clinical evaluable
Monomicrobial
241/279
139/161
86.4 (81.8–90.2)
86.3 (80.0–91.2)
231/261
133/150
88.5 (84.0–92.1)
88.7 (82.5–93.3)
–2.1 (–8.1 to 3.8)
–2.3 (–10.2 to 5.7) <0.001
0.5378

cure was reported as 86.5% and Polymicrobial 102/118 86.4 (78.9–92.0) 98/111 88.3 (80.8–93.6) –1.8 (–11.2 to 7.6) –2.1 (7.7 to 3.5)a

88.6% for Tigecycline and

mMITT 318/377 84.4 (80.3–87.9) 304/360 84.4 (80.3–88.0) –0.1 (–5.6 to 54) 1.0000
vancomycin–aztreonam, respectively Monomicrobial
Polymicrobial
185/217
133/160
85.3 (79.8–89.7)
83.1 (76.4–88.6)
183/214
121/146
85.5 (80.1–89.9)
82.9 (75.8–88.6)
–0.3 (–7.3 to 6.8)
0.2 (–8.6 to 9.3)
<0.001

–0.1 (–5.3 to 5.2)

Conclusio

• Clinical responses to Tigecycline and vancomycin–aztreonam were similar

• Tigecycline monotherapy is as efficacious as the vancomycin–aztreonam combination in treating patients with
n

cSSTI

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents
aAdjusted difference and its 95% CI are calculated from a generalised linear model with a binomial probability function
and an identity link;
CI, confidence interval; mMITT, microbiologically modified intent-to-treat Ellis-Grosse EJ, et al. Clin Infect Dis. 2005;41(Suppl. 5):S341–53. 15
European cSSTI study: overview
• Study aim
– To assess the efficacy of Tigecycline as monotherapy or in combination with Disease severity at baseline in patients with cSSTI a
other antibacterials in the treatment of cSSTI in clinical practice 100
• Study design 90

Patients with apache ii score >15 or

– Data from 254 cSSTI patients treated with Tigecycline were pooled from five 80
70
European observational studies across 2006–2011
57.1

sofa score ≥7 (%)

60 55.5
• Objectives 50
41.2
– To evaluate the efficacy of Tigecycline in patients with cSSTI, treated in the 40
routine hospital care setting in non-interventional, observational studies 30
 Patient outcome was defined as response or non-response to treatment: 20
• Response – patients assessed as ‘cured’ or ‘improved, with no further antibiotic required’ 10 4.9
0
• Non-response – ‘failure’ or ‘improved, with further antibiotic required’ 0
Germany Italy Spain-1 France Spain-2
• Patients whose outcome could not be assessed for any reason were assigned an outcome of (n=146) (n=41) (n=4) (n=17) (n = 14)
‘indeterminate’
• Patients who died following a successful response to Tigecycline at EOT were counted as
‘responders’ and patients who died before or at EOT were counted as ‘non-responders’
Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents
aDisease severity was assessed by APACHE II score in Germany, Italy, Spain-1 and Spain-2, and by SOFA score in France
APACHE, acute physiology and chronic health evaluation; EOT, end of treatment;
SOFA, sequential organ failure assessment Montravers P, et al. J Antimicrob Chemother. 2013;68(Suppl. 2):ii15–24. 16
European cSSTI study: results
Clinical response at EOT in patients with cSSTI who received
the standard dose of Tigecycline alone or in combination

• The main three reasons for use of Tigecycline in these patients

120
were: 100
100.0
91.4 88.9 86.7
– Failure of previous therapy 79.5
75.0

Clinical response (%)

80
62.5 62.5 63.6 63.5
– Suspicion of resistant pathogens 60 57.1
50.0

– Need for broad-spectrum coverage due to polymicrobial infection 40

20

• A successful clinical response was observed for 79.6% 0

Germany Italy Spain-1 France Spain-2 Total

of all cSSTI patients who received Tigecycline alone (n=140) (n=41) (n=16) (n=16) (n=15) (n=228)

or in combination pooled across the five European studies Monotherapy Combination therapy
Conclusio

• A higher proportion of seriously ill patients were captured in these real-life observational studies than in the Phase
III trials for Tigecycline
n

• Following Tigecycline treatment, overall clinical outcomes were good, even for critically ill patients

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

Montravers P, et al. J Antimicrob Chemother. 2013;68(Suppl. 2):ii15–24. 17

Global cIAI study: overview

• Study aim
– To assess the safety and efficacy of Tigecycline for the treatment of cIAI as compared to treatment with imipenem–cilastatin
• Study design
– Worldwide study, including patients from the US, Canada, Latin America, Europe, Asia and South Africa
– Data from 1,642 patients with cIAIs were pooled from two Phase III clinical trials where patients were randomised to receive either
Tigecycline or imipenem–cilastatin for 5–14 days
• Objectives
– To evaluate the findings of two Phase III, multicentre, double-blind, randomised trials, comparing clinical efficacy and safety
of Tigecycline monotherapy with imipenem–cilastatin therapy in patients with cIAI
 Primary endpoint was the clinical response at the test-of-cure visit (12–42 days after therapy)
 Patient’s response was categorised as:
• Cure – IAI process resolved
• Failure – additional antibacterial therapy required/additional surgical or radiological intervention required/death due to infection occurred/extended treatment course required/
premature discontinuation of study
• Indeterminate – patient was lost to follow-up/died within 48 hours after first dose/died after 48 hours due to non-infection-related reasons
Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

IAI, intra-abdominal infection Babinchak T, et al. Clin Infect Dis. 2005;41(Suppl. 5):S354–67. 18
Global cIAI study: results
Population Tigecycline Imipenem–cilastatin Difference Test for Test for
(Tigecycline & noninferiority differences
imipenem– p
• Clinical cure rates for the ME population No. of
patients/
Percentage of
patients (95% CI)
No. of
patients/
Percentage of
patients (95% CI) cilastatin, %
(95% CI)
were 86.1% for Tigecycline versus 86.2% total total

for imipenem–cilastatin
(95% CI, -4.5% to 4.4%, p<0.0001) Clinically evaluable
Overall
594/685 86.7 (83.9–89.2) 607/697 87.1 (84.4–89.5) –0.4 (–4.1 to 3.3) <0.0001 0.9003
–0.3 (–3.8 to 3.3)a

• Clinical cure rates for the MITT population cMITT 639/801 79.8 (76.9–82.5) 656/800 82.0 (79.2–84.6) –2.2 (–6.2 to 1.8) <0.0001 0.2851
Overall –2.0 (–5.9 to 1.8)
were 80.2% for Tigecycline, versus 81.5%
Microbiologically
for imipenem–cilastatin evaluable 441/512 86.1 (82.8–89.0) 442/513 86.2 (82.9–89.0) 0.0 (–4.5 to 4.4) <0.0001 1.0000
Monomicrobial 166/180 92.2 (87.3–95.7) 175/194 90.2 (85.1–94.0) 2.0 (–4.3 to 8.3)
(95% CI, -5.8% to 3.2%, p<0.0001) Polymicrobial 275/332 82.8 (78.3–86.7) 267/319 83.7 (79.2–87.6) –0.9 (–6.8 to 5.1)
Overall 0.6 (–3.5 to 4.6)a
• Nausea, vomiting and diarrhoea were the
mMITT 506/631 80.2 (76.9–83.2) 514/631 81.5 (78.2–84.4) –1.3 (–5.8 to 3.2) <0.0001 0.6167
most frequently reported adverse events Monomicrobial 204/241 84.6 (79.5–89.0) 211/247 85.4 (80.4–89.6) –0.8 (–7.5 to 5.9)
Polymicrobial 302/390 77.4 (73.0–81.5) 303/384 78.9 (74.5–82.9) –1.5 (–7.5 to 4.5)
for both treatment options Overall –1.2 (–5.4 to 3.1)a
Conclusio

• Tigecycline was an efficacious and well-tolerated monotherapy option for the treatment of patients with cIAI
n

• Efficacy was comparable to that of imipenem–cilastatin

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents
aAdjusted difference and its 95% CI were calculated from a generalised linear model with a binomial probability function
and an identity link
ME, microbiologically evaluable; MITT, modified intent-to-treat Babinchak T, et al. Clin Infect Dis. 2005;41(Suppl. 5):S354–67. 19
European cIAI study: overview

• Study aim Disease severity at baseline in patients with cIAI

– To determine the efficacy of Tigecycline as monotherapy or in combination 100
with other antibacterials for the treatment of cIAIs in the routine 90
hospital care setting 80

Patients with apache ii score >15

71.9
• Study design 70 66.1

or sofa score ≥7 (%)

– Data from 785 cIAI patients treated with Tigecycline were pooled 60
52.6
from five European observational studies (2006–2011) 50 48.1

• Objectives 40

– To evaluate the clinical response rate of cIAI patients treated with Tigecycline 30

depending on disease severity, infection origin and therapy regimen 20

– Clinical outcome was defined as: 10

2.9
 Response – cured/improved with no further treatment required 0
Germany Italy Spain-1 France Spain-2
 Non-response – failure or improved with further treatment required (n=386) (n=162) (n=34) (n=76) (n=32)
 Indeterminate – clinical outcome could not be assessed for any reason

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

Eckmann C, et al. J Antimicrob Chemother. 2013;68(Suppl. 2):ii25–35. 20

European cIAI study: results
Clinical outcome at EOT in patients with cIAI who received the standard dose of Tigecycline alone or in combination

100 100
• Clinical response rates at the EOT 90
91.3
90 82.6
92.7 89.2
81.5 78.4 80.6
were: 80 76 77.4 80 74 68 73.2
70 67.7 70 66.7
63.5
– 77.4% all patients 60
61.6
60 57.1 57.1

Clinical response (%)

Clinical outcome (%)
– 80.6% monotherapy patients 50 50
40 40
– 73.2% combination therapy 30
21.9
29
30
12.3 18.5
20 16.4 14.2 20
– 75.2% for nosocomial infection 11.7 8.5
10 3.3 5.4 3.2 10
0.0
– 75.8% for an APACHE II score >15 0
Ger- Italy Spain-1 France Spain-2 Total
0
Ger- Italy Spain-1 France Spain-2 Total
many (n=162) (n=92) (n=73) (n=31) (n=733) many (n=162) (n=92) (n=73) (n=31) (n=733)
– 54.2% for a SOFA score ≥7 (n=375) (n=375)
Response Non-response Indeterminate Monotherapy Combination therapy
Conclusio

• Severity of illness, as defined by APACHE II or SOFA score at baseline, was a predictor of mortality in this study
• In clinical practice, Tigecycline achieved favourable clinical response rates in seriously ill patients with cIAI
n

• Clinical outcomes were good for patients treated both with monotherapy or in combination

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

Eckmann C, et al. J Antimicrob Chemother. 2013;68(Suppl. 2):ii25–35. 21

United States cIAI study: overview

• Study aim
– To evaluate short- and long-term outcomes in a group of seriously ill patients with cIAI
• Study design
– A retrospective, observational study using a large database to examine data from 2,424 patients regarding the effectiveness of Tigecycline use
compared with other antibiotic therapies (2009–2012). Propensity scoring was used to reduce treatment-selection bias
– The clinical practice database contains patient data from >600 hospitals in the United States
• Objectives
– To examine the efficacy of Tigecycline in seriously ill patients with cIAI through a large clinical practice database
 The primary health outcome was measured as either treatment success or failure
• Success – patient was alive for at least 30 days following the first cIAI procedure OR discharged alive within 30 days without requiring a second surgical intervention
• Failure – if neither of the conditions above were met
 Other outcomes:
• Hospital LOS – total number of days in hospital
• ICU LOS – number of days the patient received treatment in the ICU
• Requirement for re-admission
Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

ICU, intensive care unit Solomkin J, et al. Surg Infect (Larchmt). 2016;17(4):402–11. 22
United States cIAI study: results
Tigecycline Other antibiotic therapy p
• Treatment was successful in 70.3% (n=606) n/N (%) (n=1,818) n/N (%)
APR-DRG severity of illnessa
of Tigecycline-treated patients and 71.2% Mild (1) 1/1 (100) 1/1 (100) 1.0000
Moderate (2) 60/63 (95.2) 159/168 (94.6) 0.8559
of patients receiving other antibiotics Major (3) 152/178 (85.4) 445/508 (87.6) 0.4512
Extreme (4) 213/364 (58.5) 689/1,141 (60.4) 0.5263
• Treatment failure was associated with a APR-DRG risk of deatha
Mild (1) 21/22 (95.5) 47/55 (85.5) 0.2173
greater need for all-cause re-hospitalisation Moderate (2)
Major (3)
101/113 (89.4)
142/171 (83.5)
284/315 (90.2)
401/496 (80.8)
0.8134
0.5248
at 30 days and 180 days Extreme (4) 162/300 (54.0) 562/952 (59.0) 0.1237
Vasopressor/mechanical ventilator use
• No differences were observed between Vasopressor use
Mechanical ventilator use
135/244 (55.3)
135/250 (54.0)
439/777 (56.5)
438/774 (56.5)
0.7476
0.4734
cIAI-related re-hospitalisation and
discharge status

• With propensity score matching to balance risk of treatment failure, Tigecycline-treated patients with diagnosis
Conclusio

of cIAI were similar to patient populations treated for cIAI with other antimicrobial regimens
n

• Similar outcomes were demonstrated between treatment with Tigecycline and other antibiotics as expressed
by treatment success, need for re-admission at 180 days and similar 30-day discharge status

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

Algorithm-based and takes into consideration ICD-9 diagnostics, age, gender, discharge data and days on mechanical ventilation;
a

APR-DRG, all patient refined diagnosis-related group; ICD, international classification of diseases Solomkin J, et al. Surg Infect (Larchmt). 2016;17(4):402–11. 23
Safety and Tolerability: Overview

• In clinical trials, the most common medicinal product-related TEAEs were reversible nausea (21%) and vomiting (13%),
which usually occurred early (on treatment days 1 or 2) and were generally mild or moderate in severity
• In clinical studies in cSSTI, cIAI, diabetic foot infections, nosocomial pneumonia and studies in resistant pathogens, a
numerically higher mortality rate among Tigecycline-treated patients has been observed as compared to the comparator
treatment
– In all Phase III and IV (cSSTI and cIAI) studies, death occurred in 2.4% (54/2,216) of patients receiving Tigecycline and 1.7% (37/2,206) of patients
receiving active comparators
– The causes of these findings remain unknown, but poorer efficacy and safety than the study comparators cannot be ruled out
• In Phase III and IV cSSTI and cIAI clinical studies, infection-related serious AEs were more frequently reported for subjects
treated with Tigecycline (7.1%) versus comparators (5.3%)
• Significant differences in sepsis/septic shock with Tigecycline (2.2%) versus comparators (1.1%) were observed
• Anaphylaxis/anaphylactoid reactions, potentially life-threatening, have been reported with Tigecycline

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

AE, adverse event; TEAE, treatment-emergent adverse event Latest BPOM Approved [TYGACIL] Local Product Document_[2021] 24
Safety and Tolerability: Continued

• Glycylcycline-class antibiotics are structurally similar to tetracycline-class antibiotics

– Tetracycline-class adverse reactions may include photosensitivity, pseudotumour cerebri, pancreatitis and antianabolic action, which has led to increased
BUN, azotaemia, acidosis and hyperphosphataemia
• AST and ALT abnormalities in Tigecycline-treated patients were reported more frequently in the post-therapy period than
in those in comparator-treated patients, which occurred more often on therapy
• Experience in the use of Tigecycline for treatment of infections in patients with severe underlying diseases is limited
– In clinical trials in cSSTI, the most common type of infection in Tigecycline-treated patients was cellulitis (59%), followed by major abscesses (25%)
– In clinical trials in cIAI, the most common type of infection in Tigecycline-treated patients was complicated appendicitis (50.3%)
– Limited experience is also available in treating patients with concurrent bacteraemia. Therefore, caution is advised when treating such patients
• Paediatric population
– Very limited safety data were available from two pharmacokinetic studies
– No new or unexpected safety concerns were observed with Tigecycline in these studies

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents

ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen Latest BPOM Approved [TYGACIL] Local Product Document_[2021] 25
Key Take-Aways
• Tigecycline is an intravenous, broad-spectrum glycylcycline antibiotic indicated in adults from the
age of 18 years for the treatment of cSSTI and cIAI1
• Tigecycline is well tolerated and efficacious in patients with cSSTI, even for critically ill patients2,3
• Clinical response rates were similar for cSSTI patients treated with Tigecycline or
vancomycin–aztreonam3
• Tigecycline is an efficacious and well-tolerated treatment option for cIAI patients4,5
• Similar outcomes were achieved for cIAI patients through treatment with Tigecycline or other
antibiotics as expressed by treatment success, the need for re-admission at 180 days and similar
30-day discharge status6
• A higher proportion of seriously ill patients were captured in the European real-life observational
studies (cIAI and cSSTI) than in the Phase III trials for Tigecycline2,5

Tigecycline should be used only in situations where other alternative antibiotics are not suitable. Consideration should be given to official guidance on the appropriate use of antibacterial agents
1.Latest BPOM Approved [TYGACIL] Local Product Document_[2021]; 2. Montravers P, et al. J Antimicrob Chemother. 2013;68(Suppl
2):ii15–24;
3. Ellis-Grosse EJ, et al. Clin Infect Dis. 2005;41(Suppl. 5):S341–53; 4. Babinchak T, et al. Clin Infect Dis. 2005;41(Suppl. 5):S354–67;
5. Eckmann C, et al. J Antimicrob Chemother. 2013;68(Suppl. 2):ii25–35; 6. Solomkin J, et al. Surg Infect (Larchmt). 2016;17(4):402–11. 26
Abbreviated Prescribing Information

Indikasi: 1) infeksi kulit dan jaringan kulit komplikata yang disebabkan oleh Staphylococcus aureus (methicillin-susceptible and -resistant isolates), termasuk kasus dengan concurrent
bacteremia, Streptococcus agalactiae, Streptococcus anginosus grp. (termasuk S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella
pneumoniae, dan Bacteroides fragilis; 2) infeksi intra-abdominal komplikata yang disebabkan oleh Citrobacter freundii, Enterobacter cloacae, Escherichia coli (includes ESBL producing
isolates), Klebsiella oxytoca, Klebsiella pneumoniae (includes ESBL producing isolates), Enterococcus faecalis (vancomycin susceptible isolates only), Staphylococcus aureus (methicillin-
susceptible and -resistant isolates), termasuk kasus dengan concurrent bacteremia, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides
fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros . Dosis dan Pemberian: initial dose 100 mg,
diikuti dengan 50 mg setiap 12 jam. Infus IV harus diberikan rata-rata selama 30-60 menit setiap 12 jam. Durasi pemberian yang disarankan untuk infeksi intra-abdominal & jaringan kulit
adalah 5 – 14 hari. Tidak ada penyesuaian dosis pada pasien dengan gangguan fungis hati ringan hingga moderat. Pada pasien dengan gangguan fungsi hati berat, dosis disesuaikan
menjadi 100 mg diikuti dengan 25 mg setiap 12 jam, dan diberikan secara hati-hati dengan pemantauan. Tidak ada penyesuaian dosis pada pasien dengan gangguan fungsi ginjal maupun
pasien yang menjalani hemodialisa. Profil keamanan dan manfaat penggunaan pada pasien usia di bawah 18 tahun belum diketahui. Oleh karena itu, Tygacil tidak direkomendasikan
untuk penggunaan pada pasien usia di bawah 18 tahun. Peringatan dan Perhatian: reaksi anafilaktik, pasien dengan riwayat hipersensitif terhadap antibiotic kelas tetrasiklin, dapat
berbahaya bagi janin pada ibu hamil, diskolorasi permanen pada gigi jika diberikan pada usia perkembangan gigi, colitis pseudomembran, monoterapi pada pasien dengan komplikasi
infeksi intra-abdominal, pankreatitis akut. Kontraindikasi: hypersensitive terhadap Tigecycline Efek samping: efek samping yang serupa dengan tetrasiklin dapat terjadi (pseudotumor
cerebri, pankreatitis, dan aksi anti-anabolik). Treatment-emergent adverse reactions: mual dan muntah. Efek samping yang dilaportkan: prolonged activated partial thromboplastin time
(aPTT), prolonged prothrombin time (PT), increased international ormalized ratio (INR), thrombocytopenia, reaksi anafilatik, bilirubinemia, peningkatan Blood Urea Nitrogen (BUN),
hipoproteinemia, hipoglikemia, pusing, phlebitis, thrombophlebitis, pneumonia, mual, muntah, diare, anoreksia, nyeri abdominal, dyspepsia, pankreatitis akut, peningkatan AST dan ALT
serum, jaundice, hepatic cholestasis, pruritus, kemerahan, reaksi kulit berat termasuk Stevens-Johson Syndrome, sakit kepala, inflamasi, nyeri dan udem pada titik injeksi dan
penyembuhan yang abnormal, peningkatan amilase serum.
•1. Latest BPOM Approved [TYGACIL] Local Product Document_[2021]

27