Antibiotic Optimization in cIAI

Management
Slide Reference 2017
 The BUGS “perfect storm”

• MRSA

• VRE

• MDR A. baumannii

• MDR P. aeruginosa

• ESBL(+) Enterobacteriaceae

• Carbapenemase(+)
Enterobacteriaceae

IDSA Public Policy. Clin Infect Dis. 2011;52(Suppl 5):S397-S428.

ESBL, Extended-Spectrum Beta-Lactamases; MDR, multidrug resistant; MRSA, Methicillin-
resistant. Staphylococcus aureus; PR, penicillin resistant; VRE, Vancomycin-resistant
Enterococcus. 2
 Bacterial resistance represents a
global public health concern
Regional incidences of Gram-negative resistant
pathogens Escherichia coli
Region Klebsiella Enterobacter spp.
ESBL Amoxicillin- pneumoniae ESBL Ceftriaxone-resistant
clavulanate resistant Levofloxacin-resistant
Global 27.0% 56.9% 48.1%
Latin America 34.9% 55.8% 58.6%

Date of preparation May 2016 PP-TYG-GLB-

North Asia 15.0% 51.9% 38.4%
South Asia 28.6% 51.6% 88.6%
Africa and the 28.7% 37.7% 20.0%
Middle East
EU 61.1% 59.8% 30.0%
US 24.0% 7.34% 33.3%

TEST resistance data using FDA-approved and EUCAST criteria. TEST is a global multi-center surveillance study designed to assess the in
vitro activity of tigecycline and comparators against a range of important pathogens.
ESBL, extended-spectrum β-lactamase; EU, European Union; EUCAST, European Committee on Antimicrobial Susceptibility Testing; FDA,
Food and Drug Administration; TEST, Tigecycline Evaluation and Surveillance Trial; US, United States.
TEST. Available at: www.testsurveillance.com [Accessed January 2016]. 3
 Rise of resistance and antibiotic
pipeline: The paradox
Resistance rates Number of new antibiotics
selected
for pathogens2 approved in the US1
70 35
60
Resistant (%)

30
50
40 25
30
20

Number
20
10 15
0
1970 1980 1990 2000 2010 10
S. aureus resistant to methicillin
5
Enterococcus resistant to vancomycin
P. aeruginosa resistant to imipenem
0
Acinetobacter spp. resistant to
1980–1989 1990–1999 2000–2009
imipenem Candida spp. resistant to
fluconazole

• From 1983 to 1987, 16 new antibiotic agents became available versus just 2 between
2008 and 2012 in the USA3
• Only 2 new anti-Gram-negative agents have become available since 2010
1. Centers for Disease Control and Prevention (CDC). Atlanta: CDC; 2013. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. Accessed May 9, 2014; 2.
Wenzel RP, et al. Infect Control Hosp Epidemiol. 2008;29:11; 3. Spellberg B. APUA Newsletter. 2012;30:8-10. http://www.tufts.edu/med/apua/news/news-newsletter-vol-30-no-1-2.shtml.
Accessed December 11, 2014.
Najy Alsayed.
4
 Greatest unmet treatment need is for
MDR Gram-negatives
Severity of unmet medical need1a • Gram-negative bacteria
5 are highly adaptive, often
possessing multiple
mechanisms of resistance2
4
• Selective antimicrobial
pressure favors
Mean score

3 amplification of resistant
Gram-negative bacteria

2 • There is increasing drug

resistance in the absence
of effective therapies
1
• Gram-negative bacteria
features, coupled with the
0 absence of new drug
MDR Gram- MRSA MDR Aspergillus MDR development, have
negatives TB gonorrhea created a “perfect storm”
Figure adapted from Hersh (2012).
a. Ranked from 1 (least severe) to 5 (most severe).
MDR, multidrug resistance; MRSA, methicillin-resistant Staphylococcus aureus; TB,
tuberculosis.
1. Hersh et al. Clin Infect Dis. 2012;54:1677-8; 2. Peleg and Hooper. N Engl J Med.
2010;362:1804-13. 5
 “ESKAPE” pathogens

Enterococcus faecium VR
Staphylococcus aureus MR
Klebsiella pneumoniae KPC
Acinetobacter baumannii MDR
Pseudomonas aeruginosa MDR
Enterobacteriaceae ESBL

The ESKAPE bugs cause the majority of hospital

infections and they escape the effects of antibiotics

Rice LB. J Infect Dis. 2008;197:1079; Boucher HW, et al. Clin Infect Dis.
2009;48:1;LR. Clin Infect Dis. 2009;49(6):992-3.
Peterson,
6
 Bad bugs and tigecycline

Enterococcus faecium
Staphylococcus aureus
Clostridium difficile
Acinetobacter baumannii

Pseudomonas
aeruginosa

Enterobacteriaceae1
Tigecycline
spectrum
1. included ESBL and carbapenemases producing.
Rice LB. J Infect Dis. 2008;197:1079.
Boucher HW, et al. Clin Infect Dis. 2009;48:1.
Peterson, LR. Clin Infect Dis. 2009;49(6):992-3.
7
 Broad/extended spectrum antimicrobials
available for monotherapy
Antibiotic Gram- Gram- Resistant Resistant Anaerobe Pseudo
negative positive Gram- Gram-
negative positive
β-Lactam /
β-Lactamase
Inhibitor
3rd-gen. Cephs

Tigecycline No proteus
No providencia
Glycopeptides

Carbapenems

Quinolones

Varies by product within

class In vitro activity

No in vitro activity
8
 Incidence of cIAI in Indonesia
Percentage (%)

43.5

21.7
17.4

8.7

Perforation Peritonitis Abses Shock

Kasminata l. Gambaran Karakteristik Penderita Ileus Obstruktif Rawat Inap di RSUD Raden Mattaher Jambi
2013.Rsud jambi.
Wahjono, H (2007). Peran Mikrobiologi Klinik Pada Penanganan Penyakit Infeksi. Thesis. Universitas Diponegoro.
 Abdominal infections in ICU characteristics,
treatment and outcome

cIAI, Complicated Intra-Abdominal Infection; ICU, Intensive Care Unit; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure
Assessment. De Waele J, et al. BMC Infect Dis 2014;14:420.
1
 Intra-abdominal infections clinical
classification

ESBL, extended spectrum beta lactamase; HAP, healthcare-associated peritonitis; MRSA, methicillin resistant Staphylococcus
aureus; VRE, vancomycin-resistant Enterococci.
Adapted from: 1. Weigelt J. Clev Clin J Med. 2007;74 (Suppl 4):S29–37; 2. DiPiro JT, Rogers DA. Intra-abdominal infections. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 3rd ed. Stamford, Conn: Appleton & Lange;1997;2148.
1
 Decision matrix:
Likelihood of resistant pathogens
in cIAI (MDR) Acineto-
MRSA VRE ESBL KPC, MBL Pseudo-
bacter spp.
monas

Primary peritonitis +++ + ++ ‒ ‒ ‒

Secondary peritonitis:
community acquired ‒ ‒ + ‒ ‒ ‒
Secondary peritonitis:
postoperative + ++ +++ + + ‒

Tertiary peritonitis ++ +++ +++ + ++ ‒

CA-cIAI without risk factors ‒ ‒ – ‒ ‒ ‒

CA-cIAI with risk factors ‒ ‒ + ‒ ++ ‒

Healthcare-associated cIAI + ‒ ++ ‒ ++ +

– = very low (<1 % isolated specific organism in affected subgroup); + = low (1–5 %); ++ = moderate (5–10 %); +++ = high (>10 %).
CA, community-acquired; cIAI, complicated intra-abdominal infection; ESBL, extended-spectrum β-lactamase; KPC, K. pneumoniae carbapenemase;
MBL, metallo-β-lactamases; MDR, multi-drug resistant; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococcus.
Adapted from Eckmann C. European Infectious Disease, 2012;6:22–7.
 Management Principles in cIAI
• Rapid diagnosis1
• Identification of high-risk patients1
• Fluid resuscitation2
• Empiric broad-spectrum antimicrobial therapy3
– Antimicrobial therapy needs to be unaffected by ESBLs to maintain a
successful surgery and treatment of cIAI *
• Source control
– Percutaneous drainage2
– Surgical intervention4

1. Solomkin JS, et al. Clin Infect Dis. 2003;37:997-1005.

2. Barie PS. J Chemother. 1999;11:464-477. * Babinchak T, et al. Clin Infect Dis. 2005;41(suppl 5):S354-S367.
3. Mazuski JE, et al. Surg Infect. 2002;3:175-233. * Mayne D, et al. Diagn Microbiol Infect Dis. 2012.
4. Laroche M, et al. Eur J Clin Microbiol Infect Dis. 1998;17:542-550.
Treatment of cIAI: A disease entity
growing in complexity
Upon
Upon diagnosis,
diagnosis, management
management consists
consists
Emergence
Emergence of of ESBLs
ESBLs in
in
Treatment
Treatment of
of cIAI
cIAI isis of
of physiological resuscitation,
physiological resuscitation,
E. coli and K. pneumoniae
E. coli and K. pneumoniae
always
always challenging
challenging11 source
source control
control and
and immediate
immediate
especially
especially problematic
problematic33 initiation
initiation of
of antimicrobial
antimicrobial therapy
therapy44

Therapy
Therapy directed
directed against
against
Infections
Infections frequently
frequently polymicrobial
polymicrobial suspected
suspectedflora
flora essential
essential3,4
3,4

Spectrum
Spectrum should
shouldcover
cover Gram-negative
Gram-negative
aerobes
aerobes and
and anaerobes,
anaerobes,
Potential
Potential exists
exists for
for resistant
resistant pathogens
pathogens including
including common
common andand more
more
unusual
unusual organisms
organisms4,5
4,5

Cultures
Cultures should
should bebe routinely
routinely obtained
obtained66
Patients
Patients are
are frequently
frequently severely
severely illill or
or
present with multiple comorbidities
present with multiple comorbidities •• Knowledge
Knowledge of of local
local susceptibility
susceptibility
data is imperative
data is imperative55
•• GI
GIflora
flora of
of hospitalized
hospitalizedpatients
patients isis
profoundly
profoundly altered
altered55
Role
Role of
of enterococci
enterococci isis controversial,
controversial, •• Overgrowth
Overgrowth of of resistant
resistant
but
but cover in
cover in immunocompromized
immunocompromized species
and species isis common
common
and severely
severely illill patients
patients with
with
abscesses,
abscesses, wounds, or peritonitis
wounds, or peritonitis with
with
damaged
damaged heart
heart valves
valves isis acceptable
acceptable22

cIAI, complicated intra-abdominal infection; ESBLs, Extended-spectrum β-lactamase-producing Enterobacteriaceae; GI, gastrointestinal
1. Golan Y. BMC Infect Dis. 2015;15:313. 2. O’Driscoll, Crank CW. Infect Drug Resist. 2015;8:217–30. 3. Skrupky LP et al. Expert Opin
Pharmacother. 2013;14:1933–47. 4. Marshall JC. Microbes Infect. 2004;6:1015–25. 5. Dupont H. Int J Infect Dis. 2007;11 Suppl 1:S1–6;
6. Sartelli M, et al. World J Emerg Surg 2013;8:3.
 Antibiotic therapy of cIAI: The need to be
right from the start
Immediate initiation is critical1
Patients with septic shock reported a 7.6% increased risk of death for
every 1-hour delay in administration of appropriate antibiotics relative
to the onset of hypotension
Inappropriate initial antibiotic selection is associated with higher rates
of therapeutic failure, surgical site infection, re-operation, death, LOS, length of
IV antibiotic therapy, and additional inpatient charges 2

Clinical
Clinical factors
factors associated
associated with
with treatment
treatment failure
failure include:
include:3,4
3,4

Delay in initial source Comorbidities and

Poor nutritional Failure of
control procedure Advanced age degree of organ
status source control
(>24 h) dysfunction
Degree of peritoneal High severity
Inappropriate
involvement (diffuse Hypoalbuminemia Malignancy of illness
antibiotic coverage
vs local peritonitis) (APACHE II score ≥15)

cIAI, complicated intra-abdominal infection, LOS, length of stay; IV, intravenous.

1. Kumar A et al. Crit Care Med. 2006;34:1589–96. 2. Membrilla-Fernández E et al. Surg Infect. 2014;15:806–14. 3. Skrupky LP et al. Expert Opin Pharmacother. 2013;14:
1933–47. 4. Tellor B et al. Surg Infect. 2015;16(6):785–93.
 Treatment options for cIAI caused by
ESBL-producing bacteria
Drug Advantages Disadvantages
Meropenem • High clinical success • “Overuse” results in increased
Imipenem / Cilastatin rates Inexpensive carbapenem resistance

Ertapenem • High clinical success rates • Limited activity against

Pseudomonas spp.

Piperacillin / • Favourable clinical response • Varying susceptibility

Tazobactam in recent trials rates (around 70%)
• Well known and well tolerated • Varying clinical success
rates
Tigecycline • Favourable clinical results in recent • Increased mortality discussion
trials with severely ill patients • Lack of activity against
• Broad range of activity Pseudomonas and
against resistant rods Proteus spp.

Ceftolozane / • High CCR in cIAI due to • Pricing

Tazobactam ESBL-producers • DATA about severely ill
• Broad range of activity patients lacking

CCR, clinical cure rate; cIAI, complicated intra-abdominal infection; ESBL, extended-spectrum beta
Adapted
lactam. from: Eckmann C, Solomkin J. Expert Opin Pharmacother 2015;16(2):271–80.
18
 Risk factors for antibiotic
treatment failure

Adapted from: Guirao X et al. Cir Esp 2010;87:63–81.

Guidelines for the antibiotic
management of complicated intra-
abdominal infections
Infectious Diseases Society of America1
Regimen Mild-to-moderate severity: perforated or High risk or severity: severe physiologic disturbance,
abscessed appendicitis and other infections advanced age, or immunocompromized state
of mild-to-moderate severity

Single agent Cefoxitin, ertapenem, moxifloxacin, Imipenem/cilastatin, meropenem, doripenem, and

tigecycline and ticarcillin/clavulanic acid piperacillin/tazobactam

Combination Cefazolin, cefuroxime, ceftriaxone, Cefepime, ceftazidime, ciprofloxacin, or levofloxacin,

cefotaxime, ciprofloxacin, or levofloxacin, each in combination with metronidazole*
each in combination with metronidazolea

World Society of Emergency Surgery2

Patient type Antimicrobial agents Dosage
In stable, non-critical patients Ertapenem 1 g every 24 h (2-h infusion time)
with ESBL-associated risk factors Tigecycline 100 mg loading dose then 50 mg every 12 h
(2-h infusion time)

In critically-ill patients Meropenem 500 mg every 6 h (6-h infusion time)

with ESBL-associated risk factors or
Imipenem 500 mg every 4 h (3-h infusion time)
+
Fluconazole 600 mg LD then 400 mg every 24 h (2-h infusion time)

*Because of increasing resistance of Escherichia coli to fluoroquinolones, local population susceptibility profiles and, if available, isolate susceptibility should
be reviewed. ESBL, extended spectrum β-lactamase.
Adapted from 1. Solomkin J, et al. Clin Infect Dis 2010;50:133–164; 2. Sartelli M, et al. World J Emerg Surg 2013;8:3.
 German guidelines 2016 for cIAI

Adapted from Eckmann C. Chirurg. 2016;87:26–33.

19
Rationale to use tigecycline in cIAI

cIAI

Community- Healthcare-
acquired associated

Risk factors for MDR

No Yes Yes

ESBL-GN ESBL-GN
CRE CRE
MDR-non
MRSA
fermenters
E. faecium / E.
MRSA
20
 Tigecycline: Rational use
according to the epidemiology

Abdominal Infections

Combination
Monotherapy Monotherapy
Treatment

CA  HC  HA

CA, community-acquired infection; HA, hospital-acquired infection; HC, health care-associated infection.
21
 Tigecycline: Its role in the hospital
• Surgical site infection
• Skin infections in patients with MDR-pathogens risk factors
• Abdominal infections in high risk patients (ie, nosocomial
peritonitis)
• Targeted therapy for MDR (ESBL, CRE,
• Acinetobacter, S. malthophilia, VRE)
• Part of mixing strategy: carbapenems-sparing regimens
• Tigecycline as a tool to save carbapenems
• Tigecycline to avoid “collateral damage”

22
 Rationale for antibiotic optimization:
Balancing the needs of patient and
society

Inappropriate Indiscriminate
antibiotic use of broad-
therapy spectrum
associated antibiotics
with higher driving
mortality resistance

The important decision in antibiotic treatment turns

out to be the choice between present and future
patients
23
 Inadequate initial antibiotic treatment leads to
2- to 3-fold increased mortality in hospitalized pts

Ventilator-associated
pneumonia1 Critical illness2 Bacteraemia3
70
60.8% 61.9%
60
Hospital mortality (%)

50
42.0%
40
33.3%
30 28.4%

20 17.7%

10

0
p<0.001 p<0.001 p<0.001

1. Kollef MH, et al. Chest. 1998; 113:412-20.

2. Kollef MH, et al. Chest.1999; 115:462-74.
3. Ibrahim EH, et al. Chest. 2000; 118:146-55.
Najy Alsayed.
24
 Defining initial inadequate therapy
Initial therapy is considered to be inadequate if:
• The antibiotic did not cover the infecting pathogen(s)
• The pathogen was resistant to the antibiotic
• Dosing was not adequate
• Not adeguate tissue penetration
• Combination therapy was not used, if indicated

1. Kollef MH et al. Chest 1999;115:462-474.

2. Ibrahim EH et al. Chest 2000;118:146-155.
25
Use the best first for
choice, dosage and
exposure

26
 Treatment paradigm in
serious Gram-negative
infections
Old New
Start cephalosporins/penicillin Get it right first time
(High dose, PK/PD,
Monotherapy adeguate for extended/continous
empiric therapy infusion)
Cost efficient low dose Combination De-
Low doses = fewer side escalate
effects
Low dose = resistance
Long courses >2 weeks
Short duration: 7 to 10 days
max

27
 8

Tigecycline European
observational studies in cIAI

cIAI, complicated intra-abdominal

infection
 Study designs and clinical indications for
tigecycline use (real-life experience)
Country where study was performed

Germany Italy Spain-1 France Spain-2 Total

Study design Prospective, Prospective, Prospective, Prospective, Retrospective,
multicentre monocentre multicentre multicentre multicentre
Period September 2006– January 2007– April August 2008– September 2008– July 2006–
March 2010 2011 December 2010 May 2010 October 2011
Number of centers 137 1 12 26 15 191

Inclusion criteria Age ≥18 years Age ≥18 years Age ≥18 years Age ≥18 years Any age
Surgical ward, Any hospital ward Surgical ward Intensive care unit Intensive care unit
intensive care unit,
internal medicine
Any indication Any indication cSSTI and cIAI only Any indication Any indication

Clinical assessment 1–3 days after EOT At EOT 1–3 days after EOT At EOT or at During
or at discharge or at discharge discharge hospitalization
Follow-up period 1–3 days after EOT 30 days after EOT or Week 12 after 7 days after EOT or Until hospital
or until discharge until discharge enrolment until discharge discharge
Number of patients 1,025 317 115 156 169 1,782

Clinical indication for tigecycline use, n (%)

cIAI 418 (40.8) 162 (51.1) 94 (81.7) 78 (50.0) 33 (19.5) 785 (44.1)
cSSTI 163 (15.9) 41 (12.9) 18 (15.7) 17 (10.9) 15 (8.9) 254 (14.3)
Othera 444 (43.3) 114 (36.0) 3 (2.6) 61 (39.1) 121 (71.6) 743 (41.7)

*Includes other ‘non-cSSTI and non-cIAI’ infections; EOT, end of treatment; cIAI, complicated intra-abdominal infection; cSSTI, complicated skin and soft tissue
Bassetti M et al. J Antimicrob Chemother 2013;68(Suppl 2):ii5–ii14.
infection.
9
 Demographic data and underlying disease
in cIAI

• Mean APACHE II
Score:
16.9 ± 7.6 SD
• Mortality: 18.7%

*Percentages of comorbid conditions were calculated for patients with at least one
comorbidity; †Includes study-level data from Italy and Spain-2; APACHE, acute
physiology and chronic health evaluation; cIAI, complicated intra-abdominal
infection; CHD, coronary heart disease; COPD, chronic obstructive pulmonary
disease.
Adapted from: Eckmann C, et al. J Antimicrob Chemother. 2013;68(Suppl 2):ii25–35.
 Antibacterial agents used in
combination with tigecycline in cIAI
Total
Patients receiving combination therapy, n 355a
Agent, n (%)b
Third- / fourth-generation cephalosporins 121 (34.8)
Aminoglycosides 44 (12.6)
Carbapenems 44 (12.6)
Fluoroquinolones 67 (19.3)
Glycopeptides 15 (4.3)
Metronidazole 28 (8.0)
Penicillins 45 (12.9)

a. Denominator for percentage calculations in the total column (n=348) does not include patients in Italy.
b. Patients could receive more than one antibacterial in combination with tigecycline.
Eckmann C et al. J Antimicrob Chemother 2013;68(Suppl 2):ii25–ii35.
11
 European observational studies
clinical response to tigecycline in cIAI
Clinical response and Clinical response and
Clinical outcome
mode of infection antibiotic therapy

100 100 100

81.6 80.6
80 77.4 80 75.2 80 73.2

Clinical Response (%)

Clinical Response (%)

Clinical Outcome (%)

60 60 60

40 40 40

20 14.2 20 20
8.5

0 0 0
Total Total Total
(n = 733) (n = 733) (n = 733)

Response Non-response Community Nosocomial Monotherapy Combination therapy

Indeterminate

Tigecycline was given at standard dose, alone or in combination. Percentages were calculated for patients with non-missing data only. Response was defined as clinical cure or
improvement without additional antibiotic. Non-response was defined as failure or improvement with additional antibiotic. Patients whose response could not be ascertained
were
assigned an indeterminate outcome; cIAI, complicated intra-abdominal infection; Eckmann C et al. J Antimicrob Chemother 2013;68(Suppl 2):ii25–ii35.
12
 Conclusions

cIAI and cSSTI infections are associated with significant

morbidity and mortality1,2
cIAI and cSSTI infections are often polymicrobial3
Optimal management of infections must take into account
the presence of resistant pathogens4

Date of preparation March 2016 PP-TYG-GLB-0038

Guidelines are available to help support treatment decisions
in the management of cIAI and cSSTI5–7
Delayed and/or inadequate empiric treatment of
complicated infections may increase patient mortality8,9

cIAI, complicated intra-abdominal infection; cSSTI, complicated skin and soft tissue infections
1. Marwick, et al. J Antimicrob Chemother. 2011;66:387‒97; 2. Cardoso T, et al. Acta Med Port. 2013;26:377–84; 3. Bassetti M, et al. J Antimicrob Chemother.
2013;68(Suppl. 2):ii5–ii14; 4. Caínzos M. Clin Microbiol Infect 2008; 14(Suppl. 6): 9–18; 5.Stevens D, et al. Clin Infect Dis. 2014;59:147–59; 6. Solomkin J, et al.
Clin Infect Dis 2010;50:133–164; 7. Sartelli M, et al. World J Emerg Surg 2013;8:3; 8. Herzog T, et al. Eur J Med Res. 2010;15(12):525–532; 9. Weigelt JA. Cleve
Clin J Med. 2007;74(4):S29-S37