HAP VAP CHALLENGES

Challenges in the management of HAP-VAP
NEWER BL/BLI
Dr Amith Sreedharan
Consultant Pulmonary/Critical Care Medicine
ASTER MIMS,KANNUR

How frequent are respiratory infections
in ICU?
CNS, central nervous system; ICU, intensive care unit; UTI, urinary tract infection.
Vincent JL, et al. JAMA 2009;302:2323–29.
7087
4503
1392 1071 1011
467 332 208
540
0
10
20
30
40
50
60
Number
of
infections
Type of infection

HAP/VAP
 PNEUMONIA THAT OCCURS 48 HOURS OR MORE AFTER
ADMISSION
 HAP THAT DEVELOPS 48 HOURS AFTER
ENDOTRACHEAL INTUBATION

Top 3 most prevalent bacterial NP pathogens
Country n (%)
Documented
aetiology, n (%) Pathogen 1 (%) Pathogen 2 (%) Pathogen 3 (%)
India
29/242
(11.98) 29 (100) Enterobactericeae (37.5) Pseudomonas spp. (35) Enterococcus (7.5)
Spain 176 (21.3) 133 (75.6) S. aureus (29.6) P. aeruginosa (17.6) Haemophilus (11.4)
Germany 138 (16.7) 84 (60.9) Escherichia coli (21.7) S. aureus (15.9) Klebsiella (10.9)
Greece 117 (14.1) 74 (63.2) Acinetobacter (33.3) P. aeruginosa (19.7) S. aureus (8.6)
France 111 (13.4) 88 (79.3) S. aureus (37.8) P. aeruginosa (18.9) Haemophilus (14.4)
Turkey 91 (11.0) 81 (89.0) Acinetobacter (52.7) S. aureus (24.2) P. aeruginosa (16.5)
Belgium 74 (8.9) 38 (51.4) S. aureus (12.2) Escherichia coli (10.8) P. aeruginosa (9.5)
Italy 65 (7.8) 40 (61.5) P. aeruginosa (27.6) S. aureus (26.2) Klebsiella (12.3)
Portugal 37 (4.5) 25 (67.6) P. aeruginosa (16.2) S. aureus (21.6) Klebsiella (8.1)
Ireland 18 (2.2) 12 (66.7) S. aureus (22.2) Escherichia coli (16.7) P. aeruginosa (11.1)
NP, nosocomial pneumonia.
Koulenti D, et al. Crit Care Med 2009;37:2360–68.
Dasgupta S et al. Nosocomial infections in the intensive care unit: Incidence, risk factors, outcome and associated pathogens in a public tertiary teaching hospital of Eastern India. Indian J Crit Care Med 2015 Jan; 19(1): 14–
20.

Bad bugs in pneumonia
Pseudomonas aeruginosa MDR
Enterobacteriaceae ESBL and CRE
Enterococcus faecium VR
Staphylococcus aureus MR
Klebsiella pneumoniae KPC, OXA
Acinetobacter baumannii MDR
The ESKAPE bugs cause the majority of hospital
infections and they escape the effects of antibiotics
CRE, carbapenem-resistant Enterobacteriaceae; ESBL, extended-spectrum beta-lactamase; KPC, Klebsiella pneumoniae carbapenemase;
MR, methicillin resistant; MDR, multidrug resistant; OXA, oxacillinase; VR, vancomycin resistant.
Rice LB. J Infect Dis 2008;197:1079; Boucher HW, et al. Clin Infect Dis 2009;48:1; Peterson LR. Clin Infect Dis 2009;49:992–3.

MDR
 CDC/ECDC
 ACQUIRED NONSUSCEPTIBILITY TO ATLEAST ONE
AGENT IN THREE DIFFERENT ANTIMICROBIAL CLASSES

RISK FACTORS FOR MDR
 IV ANTIBIOTICS IN LAST 90 DAYS
 > 5 DAYS OF HOSPITALISATION
 SEPTIC SHOCK AT TIME OF VAP
 ARDS BEFORE VAP
 RRT PRIOR TO VAP

Q1. What is the most frequent resistant bug in
your experience in HAP/VAP?
1. MRSA
2. CRE
3. P. aeruginosa MDR (carbapenem-resistant)
4. A. baumannii MDR
5. ESBL-producing Enterobacteriaceae
CRE, carbapenem-resistant Enterobacteriaceae; ESBL, extended-spectrum beta-lactamase; HAP, hospital-acquired pneumonia;
MDR, multidrug resistant; MRSA, methicillin-resistant Staphylococcus aureus; VAP, ventilator-associated pneumonia.

Evolution of Gram-negative pathogens has
caused widespread drug resistance
Susceptible
Gram-negative
pathogens
Resistant E. coli
• TEM
• SHV serine
beta-lactamases Resistant E. coli,
P. aeruginosa and
Klebsiella spp.
• AcrAB
• blaSHV
• blaTEM
• AmpC-type
beta-
lactamases
Resistant E. coli,
P. aeruginosa,
Klebsiella spp.,
Enterobacter spp.
• CTX-M-15
• VIM
• IMP
• NDM-1
• Porin defects
• Metallo-beta-
lactamases
1960s
Ampicillin
1980s
Cephalosporins,
(e.g., ceftazidime and
cefotaxime)
1990s–2000s
Carbapenems
(e.g., imipenem
and meropenem)
AcrAB, drug efflux pump; AmpC, Ampicillin; CTX-M, active on CefoTaXime, first isolated in Munich; IMP, IMP-type
carbapenemase; NDM-1, New Delhi metallo-beta-lactamase; SHV, sulphydral variable beta-lactamase; TEM, TEM-type
beta-lactamase; VIM, Verona-integron encoded metallo-beta-lactamase.
Bush K & Jacoby GA. Antimicrob. Agents Chemother 2010;54:969–76; Hawkey PM. J Antimicrob Chemother 2008;62:i1–9;
Hawkey PM & Jones AM. J Antimicrob Chemother 2009;64:i3–10; Livermore DM. Clin Infect Dis 2002;34:634–40;
Olivares J, et al. Front Microbiol 2013;4:103.

ESBLs in India (2015)
Center for Disease Dynamics, Economics & Policy. 2015. State of the World’s Antibiotics, 2015. CDDEP: Washington, D.C. Available at https://cddep.org/wp-
content/uploads/2017/06/swa_edits_9.16.pdf last accessed on 11 June 2020

Carbapenems have been widely used as treatment for
serious ESBL infections exerting selection pressure
Increased MDR enterics (ESBLs)
Transmission
and spread of
resistant genes
Select carbapenem-R
strains
Increased
carbapenem use
Increased carbapenem-R strains
Pseudomonas aeruginosa
Enterobacteriaceae
Acinetobacter
ESBL, extended-spectrum beta-lactamase; MDR, multidrug resistant; R, resistant.
Bassetti M, et al. Intensive Care Med 2015;41:776–95

 Previous global priority pathogen list
(PPL) issued by the CDC1 and the Public
Health Agency of Canada2
 Also guided by pharma companies
according to perceived/unmet medical
need, pressure of investors, market size,
scientific discovery potential, and
availability of specific technologies3
 WHO global PPL issued to guide
prioritization of incentives and funding,
help align R&D priorities with public held
need and coordination in the fight
against antimicrobial resistant bacteria3
CDC, Centers or Disease Control and Prevention; PPL, priority pathogen list; R&D, research and development; WHO, World Health Organisation.
1. CDC, antibiotic resistance threats in the United States, 2013. Available at: http://www.cdc.gov/drugresistance/threat-report-2013. Accessed on 11
June 2020; 2. Garner MJ. PLoS One 2015;10:1–11; 3.Tacconelli E, et al. Lancet 2018;3:318– 27.
Global priority list of antibiotic-resistant bacteria to guide
research, discovery, and development of new antibiotics

Proportion of CR-KP in India
CR-KP, carbapenem-resistant Klebsiella pneumoniae
Center for Disease Dynamics, Economics & Policy. 2015. State of the World’s Antibiotics, 2015. CDDEP: Washington, D.C Available at https://cddep.org/wp-
content/uploads/2017/06/swa_edits_9.16.pdf last accessed on 11 June 2020

Carbapenemase trends over the years: OXA endemicity in India
Carbapenem resistant genes3 E. coli
(n=64) n (%)
K. pneumoniae
(n=75) n (%)
Total n (%)
NDM 17(26.6) 33(44) 50(31.4)
OXA-48 22(34.4) 22(29.3) 44(27.7)
NDM + OXA-48 10 (15.6) 07(9.3) 17(10.7)
Filgona et al.(2018: BHU Hospital, Varanasi) Data from various departments3
Mohanty et. al.(2016: Safdarjung hospital) - High (76.3%) (n=93) positivity amongst isolates for at least one tested carbapenemase gene
with 48.3% frequency of OXA-48 producers alone or in co-production1
1. Mohanty S, Gajanand M, Gaind R. Identification of carbapenemase-mediated resistance among Enterobacteriaceae bloodstream isolates: A molecular study from India. Indian J Med Microbiol 2017;35:421-5
2. Sharma A, Bakthavatchalam YD, Gopi R, Anandan S, Verghese VP, et al. (2016) Mechanisms of Carbapenem Resistance in K.pneumoniae and E. coli from Bloodstream Infections in India. J Infect Dis Ther 4: 293.
3. Filgona et al. Endemicity of OXA-48 and NDM-1 Carbapenemase Producing Klebsiella pneumoniae and Escherichia coli from a Tertiary Hospital in Varanasi, India. Journal of Advances in Microbiology 2018; 12(3): 1-8
Carbapenem resistant genes2 E. coli
(n=42) n (%)
K. pneumoniae
(n=134) n (%)
Total n (%)
NDM 20 (48) 36 (27) 56 (32)
OXA-48 like 8 (19) 48 (36) 56 (32)
NDM + OXA-48 like 2 (5) 20 (15) 13 (13)
Data over a period of three years from Christian Medical College, Vellore 2013 -15 at (Sharma A et al. 2016)2

Priorities for improved MDR management in ICU
Antarctica: ESICM/ESCMID recommendations
ICU, intensive care unit; MDR, multidrug resistant; TDM, therapeutic drug monitoring.
De Waele JJ, et al. Intensive Care Med 2018;44:189–96.

Combination therapy for the treatment of
bacterial nosocomial infection?
Yes or No?

Q2. When do you use combination therapy
in HAP/VAP?
1. Always
2. Only in patients with septic shock and risk factors for MDR
3. Only in patients with MDR risk factors
4. Only in patients with higher risk of P. aeruginosa infections
5. Never
HAP, hospital-acquired pneumonia; MDR, multidrug resistant; VAP, ventilator-associated pneumonia.

Newer BL/BLI combinations
ESBL AmpC KPC OXA-48 MBL
Ceftolozane–tazobactam + +/- - - -
Ceftazidime–avibactam + + + + -
AmpC, ampicillin; BL/BLI, beta-lactam/beta-lactamase inhibitor; ESBL, extended-spectrum beta-lactamase; KPC, Klebsiella pneumoniae carbapenemase; MBL, metallo beta-lactamse; OXA, oxacillinase.
Lagace-Wiens P, et al. Infect Drug Res 2014;9:13–25; Hong MC, et al. Infect Drug Res 2013;6:215–23.

Ceftazidime–avibactam
BL/BLI, β-lactam β-lactamase inhibitor; ESBL, extended-spectrum beta-lactamase; KPC, Klebsiella pneumoniae carbapenemase;
PBP, penicillin binding proteins.
1. Hayes MV, Orr DC. J Antimicrob Chemother 1983;12:119–126; 2. Ehmann DE, et al. Proc Natl Acad Sci 2012;29:11663–11668; 3. Aktaş Z, et al. Int J
Antimicrob Agents 2012;39:86–9. 4. Lagace-Wiens P, et al. Core Evid 2014;9:13–25; 5. Crandon JL, et al. Antimicrob Agents Chemother 2012;56:6137.
 Extended-spectrum cephalosporin with activity
against Enterobacteriaceae and
P. aeruginosa1
 Binds PBPs, leading to bacterial
cell lysis1
 Novel non-β-lactam/β-lactamase inhibitor with a
unique mode of action2
 High binding affinity for Class A, C and some
Class D β-lactamases (ESBLs, KPCs and AmpC),
some of which are resistant to current agents
(e.g. KPCs)3
Ceftazidime Avibactam
Ceftazidime–avibactam is the first BL/BLI to retain activity against KPC-producing isolates,
along with ESBLs, AmpC, and OXA-484,5

 Approved for:
- Complicated intra-abdominal infection
- Complicated urinary tract infection, including pyelonephritis
- Hospital-acquired pneumonia, including ventilator associated pneumonia
cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection; CRE, carbapenemase-resistant Enterobacteriaceae; GNB, Gram-negative bacteria; KPC, Klebsiella pneumoniae carbapenemase;
HAP, hospital-acquired pneumonia; MRSA, methicillin-resistant Staphylococcus aureus; NDM, New-Delhi metallo beta-lactamase; OXA, oxacillinase; VAP, ventilator-associated pneumonia.
Ceftazidime–Avibactam Summary of Product Characteristics. April 2019
Complicated urinary-tract infections:1
Gram-negative micro-organisms:
• Escherichia coli
• Klebsiella pneumoniae
• Proteus mirabilis
• Enterobacter cloacae
• Pseudomonas aeruginosa
Complicated intra-abdominal infections:1
• Citrobacter freundii
• Klebsiella oxytoca
Hospital-acquired pneumonia, including
VAP:1
• Proteus mirabilis
• Seratia marcescens
Non-susceptible bacteria include1
• Staphylococcus aureus (methicillin-
susceptible and methicillin-resistant)
• Anaerobes
• Enterococcus spp.
• Stenotrophomonas maltophilia
• Acinetobacter spp.

Antimicrobial susceptibility of Gram-negative bacteria
Molecule Enterobacteriaceae spp.
(9149)
Enterobacteriace
ae spp. without
MBL (9075)
Pseudomonas
spp. (2038)
Pseudomonas
spp. Without
MBL (1964)
Ceftazidime-
Avibactam
99% 99.8% 92.6% 96.1%
Colistin 83% 82.9% 93.5% 93.5%
MBL: Metallo-beta lactamase
In-vitro data. Kindly correlate clinically
Karlowsky JA et al. In Vitro Activity of Ceftazidime-Avibactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Asia-Pacific Countries:
Results from the INFORM Global Surveillance Program, 2012 to 2015. Antimicrob Agents Chemother Antimicrob Agents Chemother. 2018 Jun 26;62(7). .
Sahu M K et al. Incidence, microbiological profile of nosocomial infections, and their antibiotic resistance patterns in a high volume Cardiac Surgical Intensive Care Unit. Annals of
Cardiac Anaesthesia 2016;19(2):281-287
The resistance to Meropenem in nosocomial infections in Klebsiella spp., E. coli, and Pseudomonas spp.
has been as high as 72% (62/72), 72% (37/51), and 84% (43/51) respectively.
Antimicrobial susceptibility of Gram-negative bacteria isolated from patients 42 APAC medical centres (2012-15)

Plasma and ELF concentration–time profiles
Phase I study in healthy volunteers
• Ceftazidime and avibactam penetrated well into human ELF; plasma and ELF concentrations increased
approximately dose-proportionally for both agents
• Plasma levels of ceftazidime–avibactam are a good surrogate measure for lung penetration
Cohort B: AVI 1000 mg+CAZ 3000 mg
CAZ
AVI
Cohort A: AVI 500 mg+CAZ 2000 mg
1000
100
10
1
0.1
0.01
Concentration
(mg/L)
0 4 8 12 16 20 24
Plasma geometric mean concentration (n=20)
ELF median concentration (n=5)
Individual ELF data
Time after start of infusion (h)
Concentration
(mg/L)
100
10
1
0.1
0.01
0.001
0 4 8 12 16 20 24
ELF median concentration (n=5)
Individual ELF data
100
10
1
0.1
0.01
0.001
Concentration
(mg/L)
0 4 8 12 16 20 24
ELF median concentration (n=5)*
Individual ELF data
1000
100
10
1
0.1
0.01
Concentration
(mg/L)
0 4 8 12 16 20 24
ELF median concentration (n=5)*
Individual ELF data
Geometric mean (SD) plasma and median ELF concentrations (semi-log scale)
AVI, avibactam; CAZ, ceftazidime; ELF, epithelial lining fluid.
Nicolau D, et al. J Antimicrob Chemother 2015;70:2862–69.

Ceftazidime-avibactam Phase III
clinical trial programme
Double-blind randomisation (1:1):
• CAZ 2000 mg + AVI 500 mg +
metronidazole 500 mg IV q8h or
• MER 1000 mg IV + placebo q8h
Primary objective:
• RECLAIM 1 and 2:
• Assess non-inferiority of CAZ-
AVI re: clinical cure at TOC visit
in patients with ≥1 identified
pathogen (mMITT populations)
• RECLAIM 3:
• Proportion of patients with
clinical cure at TOC visit (CE
populations)
Open-label randomisation (1:1):
• CAZ 2000 mg + AVI 500 mg +
metronidazole 500 mg q8h IV or
• Best available therapy
Primary objective:
Estimate per-patient clinical
response to CAZ-AVI and best
available therapy at TOC visit in
cUTI and cIAI caused by CAZ-
resistant Gram-negative
pathogens
• CAZ 2000 mg + AVI 500 mg q8h
IV or
• DOR 500 mg + placebo q8h IV
Primary objective:
Assess non-inferiority of CAZ-AVI on
co-primary endpoints in mMITT
analysis set:
1) Resolution of UTI-specific
symptoms
2) Resolution/improvement of flank
pain
3) Per-patient microbiol eradication
and symptomatic resolution
• CAZ 2000 mg + AVI 500 mg q8h
IV or
• MER 1000 mg + placebo q8h IV
Plus open-label empiric linezolid +
aminoglycoside
Primary objective:
Assess non-inferiority of CAZ-AVI
on clinical cure rate at TOC visit in
cMITT and CE populations
RECLAIM 1, 2 and 3:
Adults with cIAI
REPRISE
Adults with CAZ-
resistant pathogens
REPROVE
Adults with nosocomial
pneumonia (including VAP)
RECAPTURE 1 and 2:
Adults with cUTI (including
acute pyelonephritis)
AVI, avibactam; CAZ, ceftazidime; CE, clinically evaluable; cIAI, complicated intra-abdominal infection; cMMIT, clinically modified intent-to-treat; cUTI, complicated urinary tract infection; DOR, doripenem; IV,
intravenous; MER, meropenem; mMITT, microbiological modified intent-to-treat; q8h, every 8 h; TOC, test of cure; UTI, urinary tract infection; VAP, ventilator-associated pneumonia.
Mazuski JE, et al. Clin Infect Dis 2016;62:1380–9; Wagenlehner F, et al. Clin Infect Dis 2016;63:754–62; Carmeli Y, et al. Lancet Infect Dis 2016;16:661–73; Torres A, et al. Lancet Infect Dis 2018;18:285-295. doi:
10.1016/S1473-3099(17)30747-8. Epub 2017 Dec 16.
Seven prospective, international,
multicentre, randomised Phase III studies

REPROVE study
• REPROVE was a prospective, multicentre,
international, randomised, double-blind,
double-dummy, Phase III study, evaluating
efficacy and safety of ceftazidime–
avibactam compared with meropenem
• It is the first Phase III study of
ceftazidime–avibactam in the treatment of
adults with NP compared to a carbapenem
comparator
•
Primary endpoint: clinical cure at the TOC
visit in the co-primary cMITT and
CE populations
CE, clinically evaluable; cMITT, clinically modified intent-to-treat; EOT, end-of-treatment; FPFU, final protocol follow-up; IV, intravenous; NI, non-inferiority; NP, nosocomial pneumonia; q8h, every 8 hours;
TOC, test-of-cure; VAP, ventilator-associated pneumonia.
Torres A, et al. Lancet Infect Dis 2018;18:285-295. doi: 10.1016/S1473-3099(17)30747-8. Epub 2017 Dec 16.
(7–14 days of IV therapy)
Hospitalised
patients aged
≥18 years with NP,†
including VAP
Diagnosis based on:
● clinical assessment
(new worsening
infiltrate on chest
X-ray within 48 h of
randomisation), and
● ≥2 respiratory signs of
pneumonia‡
Meropenem
1000 mg by 30-min IV infusion q8h
2000–500 mg by 2-h IV infusion q8h
TOC FPFU
21–25 days
after
randomisation
1:1 randomisation
EOT
(within 24 h of last IV infusion)
28–32 days
after
randomisation
12.5% NI
margin
†Defined as pneumonia with onset ≥ 48 hours after admission or <7 days after discharge from an inpatient care facility; ‡A respiratory specimen for
Gram stain and culture was required within 48 hours of randomisation. Open-label linezolid (or vancomycin) was given for Gram-positive coverage,
and/or open-label amikacin (or other aminoglycoside) for Gram-negative coverage for a minimum of 48–72 h in patients awaiting identification or
susceptibility results from the baseline culture at randomisation

Key patient and disease characteristics at
baseline (cMITT population)
Parameter Ceftazidime–avibactam (N=356) Meropenem (N=370)
Age, years, mean (SD) 62.1 (16.6) 61.9 (17.4)
Male, n (%) 268 (75) 274 (74)
Race, n (%)
White 150 (42) 163 (44)
Black or African American 1 (<1) 2 (1)
Asian 201 (56) 199 (54)
Other 4 (1) 6 (2)
Body mass index, kg/m2, mean (SD) 24.0 (6.1) 23.9 (5.2)
APACHE II score category, n (%)
<10 1 (<1) 1 (<1)
10–19 309 (87) 316 (85)
20–30 46 (13) 53 (14)
Estimated CrCl, mL/min, mean (SD) 102.6 (67.5) 100.1 (53.1)
Renal status, n (%)
Normal renal function or mild impairment (CrCl 50–150 mL/min) 286 (80) 292 (79)
Moderate or severe impairment (CrCl 16–50 mL/min) 18 (5) 18 (5)
Augmented (CrCl >150 mL/min) 50 (14) 58 (16)
NP subtype, n (%)
VAP 118 (33) 128 (35)
Non-VAP 238 (67) 242 (65)
Mechanical ventilation at baseline, n (%)
Ventilated 154 (43) 159 (43)
Non-ventilated 202 (57) 211 (57)
Prior systemic antibiotic use (in the 48 hours before randomisation), n (%)
None 122 (34) 117 (32)
>0 to ≤24 hours 185 (52) 209 (56)
>24 to ≤48 hours 49 (14) 44 (12)
APACHE, Acute Physiology And Chronic Health Evaluation; CrCl, creatinine clearance; NP, nosocomial pneumonia; SD, standard deviation; VAP, ventilator-associated pneumonia.

Primary endpoint efficacy: clinical cure rates at
TOC (CE and cMITT populations)
 Ceftazidime–avibactam was non-inferior to meropenem for the treatment of HAP/VAP
in this setting
77.4
68.8
78.1
73.0
0
20
40
60
80
100
Difference (95% CI): −0.7%
(−7.86, 6.39)
Difference (95% CI): −4.2%
(−10.76, 2.46)
Patients
with
favourable
clinical
response
(%)
Clinical cure rate at test of cure
Meropenem
CE population cMITT population
(n=199/257) (n=211/270) (n=270/370)
(n=245/356)
CE, clinically evaluable; CI, confidence interval; cMITT, clinically modified intention-to-treat; HAP, hospital-acquired pneumonia; TOC, test of cure; VAP, ventilator-associated pneumonia.
P=0.0007 P=0.0066

Microbiological response at TOC in patients with
ceftazidime-non-susceptible Gram-negative pathogens isolated at baseline
Patients, n/N (%)
Analysis
population
Ceftazidime–
avibactam
Meropenem
Difference
(95%, CI)
mMITT 27/46 (58.7) 27/54 (50.0) 8.7 (–10.91, 27.56)
eME 23/37 (62.2) 21/41 (51.2) 10.9 (–11.14, 31.90)
ME 21/30 (70.0) 18/32 (56.3) 13.8 (–10.49, 36.38)
Ceftazidime-non-susceptible includes both the CLSI-breakpoint-defined categories for ceftazidime-non-susceptible and intermediate pathogens, i.e., MIC
≥8 mg/L for Enterobacteriaceae and ≥16 mg/L for Pseudomonas aeruginosa
CI, confidence interval; CLSI, Clinical Laboratory Standards Institute; eME, extended microbiologically evaluable; EOT, end of treatment, ME, microbiologically evaluable; MIC, minimum inhibitory concentration; n,
number of patients in subgroup; N, number of patients in treatment group; mMITT, microbiologically modified intent-to-treat; TOC; test-of-cure.
Supplement to: Torres A, et al. Lancet Infect Dis 2018;18:285-295. doi: 10.1016/S1473-3099(17)30747-8. Epub 2017 Dec 16.

REPROVE INDIAN SUBSET DATA
 In line with the global REPROVE protocol, Indian patients
enrolled in the study with nosocomial pneumonia, were
randomly assigned ( 1:1) to 2.5gm Ceftazidime avibactam or
1gm of Meropenem
 Descriptively analyzed the efficacy results in the Indian
population and compared them with the overall results in the
global trial
 90 patients were included from 4 centers
Posters listing (P076): Indian experience with ceftazidime-avibactam used in the treatment of serious infections in ICU setting: Subset Analysis from REPROVE & RECLAIM Trials [Internet].
Isicem.esn.eu.2019 [cited 12 June 2019]. Available from https://isicem.esn.eu/posters_listing/see_poster/309/2019/page_2. accessed on 11 June 2020

Results
Microbiologically modified intent -to-treat (mMITT)-All patients in the MITT analysis set who had ~1 baseline Gram-negative pathogen
Microbiologically Evaluable (ME) and Extended-ME - Patients in the CE analysis set with a baseline pathogen susceptible to both study treatments (ME) or regardless of
susceptibility (Extended-ME)
TOC, test-of-cure;EOT, end-of-treatment; CE, clinically evaluable; cMITT, clinically modified intent-to-treat; MITT, modified intent-to-treat; mMITT, microbiologically modified intent-
totreat;
ME, microbiologically evaluable; CAZ-AVI, ceftazidime-avibactam
The safety and efficacy outcomes in Indian
subset treated with CAZ-AVI as part of
REPROVE study were in line with global
outcomes.
Posters listing (P076): Indian experience with ceftazidime-avibactam used in the
treatment of serious infections in ICU setting: Subset Analysis from REPROVE &
RECLAIM Trials [Internet]. Isicem.esn.eu.2019 [cited 12 June 2019]. Available from
https://isicem.esn.eu/posters_listing/see_poster/309/2019/page_2. accessed on 11
June 2020

Ceftazidime–avibactam in
carbapenem-resistant infections
 36 patients with CRE and 2 with CRPa
- The most common infections were intra-abdominal and respiratory
 60.5% life-threatening infections
 The median duration of ceftazidime–avibactam treatment was 16 days
 73.7% experienced clinical and/or microbiological cure
 Microbiological cure was associated with improved survival
 Ceftazidime–avibactam shows promising clinical results for infections for
which treatment options are limited
CRE, carbapenem-resistant Enterobacteriaceae; CRPa: carbapenem-resistant Pseudomonas aeruginosa.
Temkin E, et al. Antimicrob Agents Chemother. 2017;61(2):61:e01964–16.

Colistin versus ceftazidime–avibactam in the treatment of
infections due to carbapenem-resistant Enterobacteriaceae
 38 patients were treated first with ceftazidime–avibactam and 99
with colistin
 Respiratory (n=30, 22%) infections
 All-cause hospital mortality at 30-days
- Ceftazidime–avibactam 9%
- Colistin 32%, (p=0.0012)
 Disposition at 30 days, patients treated with
- Ceftazidime–avibactam had 64% probability of a better outcome as compared to
patients treated with colistin
 Partial credit analyses indicated uniform superiority of
ceftazidime–avibactam to colistin
Van Duin D, et al. Clin Infect Dis 2017. DOI: 10.1093/cid/cix783.

Ceftazidime–avibactam in patients with MDR P. aeruginosa
infection: compassionate-use programme in Spain
 Retrospective study from January 2016 to May 2017
 Patients (N=8) received ceftazidime–avibactam as initial or continuation therapy for
infections due to MDR and XDR P. aeruginosa on a compassionate-use basis
 Patients had hospital-acquired lower respiratory tract infection (n=5; 62.5%),
 All patients had comorbidities, with diabetes mellitus being most prevalent (62.5%)
- Median SOFA score was 4 (range 0–8)
 Clinical cure was achieved in 50% of patients, comparing favourably with results of
the REPROVE study in patients with HAP, including VAP
 Ceftazidime–avibactam may be a valuable option for serious infections due to
resistant P. aeruginosa
HAP, hospital-acquired pneumonia; MDR, multidrug resistant; SOFA, Sepsis-related organ failure assessment; VAP, ventilator-associated pneumonia; XDR, extensively drug resistant.
Rodríguez-Núñez O et al. J Glob Antimicrob Resist. J Glob Antimicrob Resist. 2018 Dec;15:136-139.; Torres A, et al. Lancet Infect Dis 2018;18:285-295.

Real-life data: therapy of pneumonia with ceftazidime–
avibactam
1. King M et al. Antimicrob Agents Chemother 2017;61:e00449-17; 2. Sousa A, et al. J Antimicrob Chemother 2018;73:3170–5; 3. Temkin E, et al. Antimicrob Agents Chemother 2017;61:e01964-16; 4.
Tumbarello M, et al. Clin Infect Dis. 2019;68(3):355‒64.
Type of study Overall population
/pneumonia
Inhospital
mortality/mortality
due to pneumonia
Microbiological cure Clinical success
King1 Multicenter
Retrospective
Cohort study1
60
16 (27%)1
19/60 (32%)1 /
9 (56%)1
32/60 (53%)1
7 (44%)1
39/60 (65%)1
9 (56%)1
Sousa2
Pure OXA2
Single center
Prospective
Observational
Cohort study2
572
15 (26%)
including 7 VAP2
8 (14%) 2 /
3 (37.5%) 2
Temkin3 Multicenter
Retrospective
Cohort study3
383
7 (18.4%)3
15 (39.5%)3/
5 (71.4%%)3
24 (63.2%)3
3 (42.9%)3
26 (68.4%)3
3 (42.9%)3
Tumbarello4 Single center
Prospective
Observational
Cohort study4
1384
13 (9%)4
47 (34.1%)4/
4 (30.1%)4

Ceftazidime–avibactam patient profile
+
Clinical entities:
Nosocomial pneumonia, complicated urinary tract
infections, complicated
intra-abdominal infections,
Risk factors for CRE + ESBL Enterobacteriaceae
– Receipt of broad-spectrum antimicrobial therapy (especially
carbapenems)
– History of long hospitalisation
– Invasive devices
– ICU admissions
Critically ill patients
Consider local epidemiological
data
• CRE (KPC and/or OXA-48)
• > 20%
• ESBL
• > 20% in E. coli and/or
Klebsiella
CRE, carbapenem-resistant Enterobacteriaceae; ESBL, extended-spectrum beta-lactamase; ICU, intensive care unit;
KPC, Klebsiella pneumoniae carbapenemase; OXA, oxacillinase.
Bassetti M, et al. Expert Rev Anti Infect Ther 2017;15:55–65.; Montravers P, Bassetti M. Curr Opin Infect Dis 2018;31:587–93

Conclusions
 In an era of increasing drug resistance new treatment modalities are required
 REPROVE data confirm the efficacy and safety of
ceftazidime–avibactam and the non-inferiority vs meropenem for the treatment
of HAP/VAP caused by ceftazidime-non-susceptible or ceftazidime-susceptible
Gram-negative aerobic pathogens
 Experience of ceftazidime–avibactam in the treatment of severe infections in
hard-to-cure carbapenem-resistant Enterobacteriaceae is accumulating,
showing 60–70% success
HAP, hospital-acquired pneumonia; MDR, multidrug-resistant; VAP, ventilator-associated pneumonia.
O’Neil J. TACKLING DRUG-RESISTANT INFECTIONS GLOBALLY: FINAL REPORT AND RECOMMENDATIONS . Available at: https://amr-review.org/. [Accessed 11June 2020 Torres A, et al. Lancet Infect Dis
2018;18:285-295. doi: 10.1016/S1473-3099(17)30747-8. Epub 2017 Dec 16; Temkin E, et al. Antimicrob Agents Chemother 2017;61:e01964-16; Tichy E, et al. Presented at 28th ECCMID, 21–24 April 2018, Madrid,
Spain. Poster O0602.

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