mdr infection

1. TACKLING THE
MENACE OF MDR
GRAM NEGATIVE
PATHOGENS WITH A
NOVEL BL-BLI: A
CASE BASED
APPROACH
Please see Summary of prescribing information on the last slide

3. Annual
Report
Antimicrobial
Resistance
Surveillance
and Research
Network
(2019)
by ICMR
Antimicrobial Resistance Surveillance and Research Network. January 2019 to December 2019. Annual
Report ICMR. Available at
https://main.icmr.nic.in/sites/default/files/upload_documents/Final_AMRSN_Annual_Report_2019_290720
20.pdf Accessed on 10Aug 2020.
The menace of gram negative organisms!

4. AMRSN report 2019
– K.pneumoniae
1. Steady increase of Klebsiella pneumoniae from 13.9% in
2016 to 17.5% in 2019
2. ~50% susceptibility rates for Meropenem
3. 93.5% susceptibility for colistin
Yearly susceptibility trend
Antimicrobial Resistance Surveillance and Research Network. January 2019 to December 2019. Annual Report ICMR. Available at
https://main.icmr.nic.in/sites/default/files/upload_documents/Final_AMRSN_Annual_Report_2019_29072020.pdf Accessed on 10 Aug 2020.
Organism Antibiotic 2016 (%S) 2017 (%S) 2018 (%S) 2019 (%S)
K.Pneumoniae
Amikacin 396/848
(46.7)
2585/5286
(48.9
4203/8274
(50.8)
6446/12878
(50.1)
Colistin 0/3 452/501
(90.2)
1069/1168
(91.5)
2198/2352
(93.5)
Meropenem 436/847
(51.5)
2480/5147
(48.2)
3831/7589
(50.5)
6005/12024
(49.9)
Imipenem 566/874
(64.8)
3136/5360
(58.5)
4256/8221
(51.8)
4962/10892
(45.6)
Piperacillin-
tazobactam
364/871
(41.8)
2209/5179
(42.7)
3256/8221
(39.6)
4811/12366
(38.9)

5. 1. EPIDEMIOLOGY &
2. SUSCEPTIBILITY TRENDS
IN RESPECTIVE HOSPITALS
FOR GRAM NEGATIVE
INFECTIONS
Points for discussion

6. CASE STUDY

7. Case
history
• 55-year-old woman
• history of type 2 diabetes mellitus & chronic
obstructive pulmonary disease, along with coronary
artery disease with a 3-vessel bypass 5 years prior
• developed new onset shortness of breath and fever
• On arrival in emergency,
– Respiratory status worsened
– Her ventilation rapidly deteriorated despite the use of
noninvasive positive pressure ventilation and she
became minimally responsive, prompting endotracheal
intubation and admission to the medical intensive care
unit
– Chest X-ray showed lobar infiltrate
Adapted from Maley J.H., Stevens J.P. (2020) Ventilator-Associated Pneumonia. In: Hyzy R., McSparron J. (eds) Evidence-Based Critical Care. Springer, Cham. https://doi.org/10.1007/978-
3-030-26710-0_29

8. WHAT WOULD BE THE NEXT
STEP?
1. START AN APPROPRIATE
ANTIBIOTIC
2. SEND CULTURE SAMPLES
3. ASSESS RISK FACTORS FOR
MDR
Points of discussion

9. Case contd • Patient started on meropenem and azithromycin
• On day 5 of the ICU, , she developed a new fever and
her oxygenation worsened
• A chest radiograph now showed diffuse, bilateral
infiltrates
• BAL sample was sent for culture and sensitivity
Adapted from Maley J.H., Stevens J.P. (2020) Ventilator-Associated Pneumonia. In: Hyzy R., McSparron J. (eds) Evidence-Based Critical Care. Springer, Cham. https://doi.org/10.1007/978-
3-030-26710-0_29

10. Importance
of local
epidemiology
• Prior to prescribing antimicrobial therapy, resistance
patterns within an institution are important to
consider, and close liaison with the microbiology
laboratory facilitates the decision-making process 1
• Awareness of the local epidemiology allows tailoring of
initial therapy according to local trends in pathology
and resistance 2
1. Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev. 2012;25(3):450-470. doi:10.1128/CMR.05041-11
2. Morris S, Cerceo E. Trends, Epidemiology, and Management of Multi-Drug Resistant Gram-Negative Bacterial Infections in the Hospitalized Setting. Antibiotics (Basel). 2020;9(4):196. Published 2020
Apr 20. doi:10.3390/antibiotics9040196

11. WHICH TESTS?
WHEN?
ADVANTAGE?
Points of discussion

12. Role of laboratory diagnosis in management of
MDR gram negative infections
• Conventional phenotypic antimicrobial
susceptibility testing (AST) methods-
provide results 36-72 h after patients'
sample collection 1
• Novel molecular methods (i.e. no
microbial growth-based methods) are
much faster, and their times to results
are 1-4h 1
• Benefit the individual patient by
enabling timely & targeted
antimicrobial optimization, which, in
turn, may lead to decreased mortality,
shortened hospital stay, and lower
hospitalization costs. 2,3,4
• Decreased use of unnecessary empirical
therapies 3
1. De Angelis G, Grossi A, Menchinelli G, Boccia S, Sanguinetti M, Posteraro B. Rapid molecular tests for detection of antimicrobial resistance determinants in Gram-negative organisms from positive blood
cultures: a systematic review and meta-analysis. Clin Microbiol Infect. 2020;26(3):271-280.; 2. Lutgring JD, Limbago BM. The Problem of Carbapenemase-Producing-Carbapenem-Resistant-Enterobacteriaceae
Detection. J Clin Microbiol. 2016 Mar;54(3):529-34 3. Messacar K, Parker SK, Todd JK, Dominguez SR. Implementation of Rapid Molecular Infectious Disease Diagnostics: the Role of Diagnostic and
Antimicrobial Stewardship. J Clin Microbiol. 2017;55(3):715-723 4. Bauer KA, Perez KK, Forrest GN, Goff DA. Review of rapid diagnostic tests used by antimicrobial stewardship programs. Clin Infect Dis.
Test method Accuracy Turn-around time * Information provided
Modified Hodge test Moderate Next day Detection of carbapenemase
activity
Carba NP test Moderate Same day Detection of carbapenemase
activity
Carbapenemase inactivation
method
High Next Day Detection of carbapenemase
activity
MALDI-TOF MS High Same Day Detection of carbapenemase
activity
PCR High Same Day Detection of specific
carbapenemase gene
Microarray High Same Day Detection of specific
carbapenemase gene
.
*Turnaround time, time to results from pure culture of isolate

13. Case contd • Culture results- Klebsiella pneumoniae
• On rapid molecular testing, OXA-48 detected
• Disc diffusion test shows susceptibility to ceftazidime
avibactam
Hypothetical scenario

14. Understanding
OXA- 48
• 11 enzyme variants have since been identified
across the world
• OXA-48b, OXA-54, OXA-162, OXA-163, OXA-181,
OXA-199, OXA-204, OXA-232, OXA-242, and OXA-
247 (OXA- 48 like variants)
• Mortality remains high in patients infected with
OXA-48-like producers
• OXA-48 - frequently reported
from E. coli and Klebsiella pneumoniae
• High level of OXA-48 resistance is associated with
co-production of extended spectrum β-
lactamase(ESBL)
• Co-production of OXA-48 is also seen with other
carbapenemase including NDM-1andVIM
Bakthavatchalam YD, Anandan S, Veeraraghavan B. Laboratory detection and clinical implication of oxacillinase-48 like carbapenemase: The hidden threat. J Global Infect Dis 2016;8:41-50

15. Identification of
carbapenemase-mediated
resistance among
Enterobacteriaceae
bloodstream isolates: A
molecular study from
India (2017)
 Consecutive, non-duplicate isolates of Escherichia coli
(EC) and Klebsiella pneumoniae from clinically
diagnosed bloodstream infections were screened for
the presence of carbapenem resistance by standard
disk-diffusion method and minimum inhibitory
concentration breakpoints
• Carbapenemase encoding genes were amplified by
polymerase chain reaction
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
387 isolates (214 K. pneumoniae, 173 EC)
tested
93 (24.03%) were found to be CRE
71 (76.3%) were positive for at least one
tested carbapenemase gene
 New Delhi metallo-β-lactamse-1 (65.6%)
 Oxacillinase (OXA)-48 (24.7%)
 OXA-181 (23.6%)
 Verona integron-encoded metallo-β-lactamase
(6.4%) and
 K. pneumoniae carbapenemase (2.1%).

16. Endemicity of
OXA-48 and NDM-
1 Carbapenemase
Producing
Klebsiella
pneumoniae and
Escherichia
coli from a Tertiary
Hospital in
Varanasi, India
(2018)
Total Isolates=293 E. coli and 236 K. pneumoniae
Multidrug resistant isolates = 391.
159 isolates (64 E. coli and 75 K. pneumoniae)= carbapenem
resistant enterobacteriaceae.
• Investigated the prevalence of OXA-48 like and NDM-1 among clinical isolates of
K. pneumoniae and E. coli
• Multiplex PCR-based detection of the blaNDM-1 and blaOXA-48
Filgona, J., Banerjee, T., & Anupurba, S. (2018). 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, 12(3), 1-8.
 50/159(31.4%) isolates were positive for NDM-1
 44/159(27.7%) for OXA-48, while
 17/159(10.7%) co-harboured NDM-1 and OXA-48 like
genes

17. Carba-R Assay on Flagged Blood Culture Samples:
Clinical Utility in Intensive Care Unit Patients with Gram
Negative Bacteremia
N=160
A total of 164 GNB were
isolated with 4 patients
having polymicrobial
bacteremia
Klebsiella pneumoniae and
Escherichia coli predominant
Carba-R was positive in
58/164 (35.36%) samples &
73/161 isolates (45.34%) were
CR on routine DST
Distribution of CR genes-
OXA-48 like (29/58-50%),
NDM (19/58-32.7%),
OXA-48 & NDM co-
expression (9/58-15.51%)
Median time to obtain report
was 30 hours 34 minutes vs.
74 hours and 20 minutes for
carbapenem resistance on
routine DST.
Based on the Carba-R report, 9.72% of patients had escalation of antibiotics (e.g. colistin) to cover CR organisms and 27.08%
had de-escalation from CR cover that had already been started
Retrospective observational study
Carba-R (FDA approved for rectal
swab specimen) was done on gram
negative bacteria (GNB) flagged
blood culture samples, in a tertiary
care Indian intensive care unit
between January 2015 and
November 2018.
Rajendran S. Xpert Carba-R Assay on Flagged Blood Culture Samples: Clinical Utility in Intensive Care Unit Patients with Gram Negative Bacteremia [Poster]
presented at ID week; October 2-6, 2019; Washington DC

18. Co-production with other beta lactamases
• Co-carriage of OXA-48 and other beta -
lactamases in 265 OXA-48-positive
Enterobacteriaceae collected in 2012 to
2015
• As many as 80% of OXA-48-positive isolates are
reported to coproduce ESBLs
• In the study, 88.7% of OXA-48-positive isolates
(n = 235) carried additional β-lactamases
capable of hydrolyzing expanded-spectrum
cephalosporins or aztreonam
• % susceptibility to meropenem ranged from 0 to
36.4%
It is important to know the local prevalence of OXA-48 and
OXA-48-like β-lactamases among clinical isolates so that
infections caused by isolates with a higher MIC value for a
carbapenem, even if the MIC does not cross the threshold
of “resistant,” should be considered for treatment options
other than carbapenems.
Kazmierczak KM, Bradford PA, Stone GG, de Jonge BLM, Sahm DF. In Vitro Activity of Ceftazidime-Avibactam and Aztreonam-Avibactam against OXA-48-Carrying Enterobacteriaceae Isolated as Part of the
International Network for Optimal Resistance Monitoring (INFORM) Global Surveillance Program from 2012 to 2015. Antimicrob Agents Chemother. 2018;62(12):e00592-18

19. EPIDEMIOLOGY OF
BETA LACTAMASES AT
RESPECTIVE
HOSPITALS
Points of discussion

20. Case contd • Culture results- Klebsiella pneumoniae
• On rapid molecular testing, OXA-48 detected
May indicate
ESBL production
Rawat D, Nair D. Extended-spectrum β-lactamases in Gram Negative Bacteria. J Glob Infect Dis. 2010;2(3):263-274. doi:10.4103/0974-777X.68531
Hypothetical scenario

21. Ceftazidime- avibactam
Ceftazidime-Third generation cephalosporin
Avibactam- non beta lactam- beta lactamase inhibitor
 First-in-class
 Inhibition of β-lactamases is covalent but reversible
(characteristic that other known β-lactamase
inhibitors lack)
 The activity of AVI is reinstated once acted
Spectrum of activity
 in vitro activity against many
important Gram-negative
pathogens
 Many ESBL, AmpC KPC and OXA-
48-producing Enterobacterales
 Drug-resistant P.aeruginosa
isolates
× Acinetobacter
× Metallo- beta lactamases
Shirley M. Ceftazidime-Avibactam: A Review in the Treatment of Serious Gram-Negative Bacterial Infections. Drugs. 2018;78(6):675-692
Dietl B, Martínez LM, Calbo E, Garau J. Update on the role of ceftazidime-avibactam in the management of carbapenemase-producing Enterobacterales. Future Microbiol. 2020;15:473-

22. Avibactam has a broad spectrum of activity2
1. Zhanel GG, Lawson CD, Adam H, Schweizer F, Zelenitsky S, Lagacé-Wiens PR, Denisuik A, Rubinstein E, Gin AS, Hoban DJ, Lynch JP. Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs. 2013 Feb 1;73(2):159-77.
2. Stachyra T, Péchereau MC, Bruneau JM, Claudon M, Frère JM, Miossec C, Coleman K, Black MT. Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-β-lactam β-lactamase inhibitor. Antimicrobial agents and chemotherapy. 2010 Dec
1;54(12):5132-8.;
3. Lagacé-Wiens P, Walkty A, Karlowsky JA. Ceftazidime–avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core evidence. 2014;9:13.
Avibactam
Class A
TEM1,2, SHV1,2

CTX-M1,2

KPC1-3

Class B IMP3, VIM3, NDM13

Class C
AmpC1,2

ACC-13, CMY-13, FOX3, 
Class D OXA 483

CTX-M, cefotaxime-β-lactamase; KPC, Klebsiella pneumoniae carbapenemase;
NDM, New Delhi metallo-β-lactamase; TEM, temoneira; SHV, sulfhydryl variable; VIM, Verona integron-encoded metallo-β-lactamase.

23. Ceftazidime - avibactam spectrum of activity
VAP, ventilator-associated pneumonia.
Zavicefta (Ceftazidime-Avibactam). Local product document. LPDZAVIC032020
Complicated urinary-tract infections:
Gram-negative micro-organisms:
• Escherichia coli
• Klebsiella pneumoniae
• Proteus mirabilis
• Enterobacter cloacae
• Pseudomonas aeruginosa
Complicated intra-abdominal infections:
Gram-negative micro-organisms:
• Citrobacter freundii
• Enterobacter cloacae
• Escherichia coli
• Klebsiella oxytoca
• Klebsiella pneumoniae
• Pseudomonas aeruginosa
Hospital-acquired pneumonia, includingVAP:1
Gram-negative micro-organisms:
• Enterobacter cloacae
• Escherichia coli
• Klebsiella pneumoniae
• Proteus mirabilis
• Seratia marcescens
• Pseudomonas aeruginosa
Non-susceptible bacteria include
• Staphylococcus aureus (methicillin-susceptible and
methicillin-resistant)
• Anaerobes
• Enterococcus spp.
• Stenotrophomonas maltophilia
• Acinetobacter spp.

24. EVIDENCE FOR
EFFICACY &
SAFETY

25. • The most frequent source of infection were IAI (28%), followed by
respiratory (26%) and UTI (25%)
• 31 (54%) patients had a severe infection
• The was no association between mortality and monotherapy with CAZ–AVI; the
recurrence rate at 90 days was 10%
• CAZ–AVI resistance was not detected in any case and only two patients
developed AEs related to treatment
• Mortality at 14 days was 14%; in multivariate analysis, the only mortality risk
factor was INCREMENT-CPE score >7 (HR 11.7, 95%
CI 4.2–20.6)
• CAZ–AVI showed promising results, even in monotherapy, for the
treatment of patients with severe infections due to OXA-48-producing
Enterobacteriaceae and limited therapeutic options
Effectiveness of CAZ–AVI as salvage therapy for treatment of infections due to OXA-48 carbapenemase-
producing Enterobacteriaceae
Sousa A, et al. J Antimicrob Chemother 2018;73:3170–3175
Study background
• An observational study of a prospectively collected cohort of adult patients
receiving CAZ–AVI
• The first treatment course of each patient was analysed
• Efficacy and safety were evaluated as 14 and 30 day mortality,
recurrence rate at 90 days, resistance development and occurrence
of AEs
• 57 patients were treated with CAZ–AVI
AEs, adverse events; CAZ–AVI, ceftazidime–avibactam; CRE,
carbapenem-resistant Enterobacteriaceae; IAI, intra-abdominal
infection; MIC, minimum inhibitory concentration; OXA, oxacillinase;
UTI, urinary tract infection
Antibiotic Susceptible isolates, n (%)
Colistin 45 (75)
Imipenem 2 (3)
Imipenem MIC <8 mg/L 27 (47)
Meropenem 1 (2)
Fosfomycin 10 (17)
Tigecycline 7 (12)
Amikacin 3 (5)
CAZ–AVI 57 (100)
Adapted from Sousa A, et al. 2018
Antimicrobial susceptibility of isolates (n=57) from patients treated with CAZ–AVI

26. • The median time from admission to isolation of CRE culture was 22.5 days in
the CAZ–AVI group and 17 days in the comparative group (P=0.7)
• A carbapenemase gene was isolated from 35 (92%) patients; the OXA-48
gene was the predominant gene identified in 28 (74%) isolates; 8 out of 10
patients in the CAZ–AVI group and 15 out of 28 in the comparative group
achieved clinical remission (P=0.14)
• At 30 days, all-cause mortality was observed in five patients in the CAZ–AVI group and 16 patients in the comparative group, accounting for 50 and 57%
respectively;
• CAZ–AVI is an alternative standard therapy for OXA-48-type CRE
Efficacy of CAZ–AVI in the treatment of infections due to CRE
Alraddadi BM, et al. BMC Infect Dis 2019;19:772
Study background
• Retrospective cohort study of patients with established CRE infections from
January 2017 until August 2018 was conducted
• All patients who received CAZ–AVI and all cultures with carbapenem-
resistant isolates were screened
• Patients who received CAZ–AVI for CRE infections were compared with
patients who received other agents
• A total of 38 consecutive patients with CRE infections were identified, age
and baseline comorbidities were similar between the two groups
CAZ–AVI, ceftazidime–avibactam;
CLABSI, central line-associated blood stream infections;
cIAI, complicated intra-abdominal infections
CRE, carbapenem-resistant Enterobacteriaceae;
cUTI, chronic urinary tract infections;
HAP, hospital acquired pneumonia; OXA, oxacillinase;
SSTI; soft tissue infection
Type of infection CAZ–AVI Comparative P value
HAP 5 (50) 14 (50) >0.99
cUTI 3 (30) 8 (28.6) >0.99
cIAI 3 (30) 5 (17.8) 0.41
Adapted from Alraddadi, et al. 2019
Baseline characteristics of patients with CRE infections who
received CAZ–AVI or different CRE specific antibiotics

27. Early use
was
associated
with
improved
outcomes
• Study byTemkin et al,
– 79% of patients with negative cultures at the end of
treatment survived until discharge
– They suggest that ‘Waiting to exhaust all other (and
potentially more toxic) treatment options before
resorting to CAZ-AVI may reduce a patient’s likelihood of
being cured’
• Study by Jorgensen et al
– Early use of CZA (within 48 hours of infection onset), was
associated with improved clinical outcomes
– Underscores the important role of rapid diagnostic
testing for early pathogen identification and
susceptibility testing
Temkin E, Torre-Cisneros J, Beovic B et al. Ceftazidime-avibactam as salvage therapy for infections caused by carbapenem-resistant organisms. Antimicrob. Agents Chemother. 61(2), e01964–16 (2017). Jorgensen SCJ, Trinh TD, Zasowski EJ et al.
Real-world experience with ceftazidime-avibactam for multidrug-resistant gram-negative bacterial infections. Open Forum Infect. Dis. 6(12), ofz522 (2019).

28. • The mortality rate was similar in patients treated with monotherapy or
combination therapy (RR=1.18, 95% CI 0.88–1.58; P=0.259)
• All studies except one reported data on the emergence of resistance to
CAZ–AVI, with a total of eight patients (4.1%) in the monotherapy and six
patients (3%) in the combination group developing
CAZ–AVI resistance
• No difference was found between the two groups when analysing the rate
of microbiological cure (64.9% for combination therapy vs. 63.4% for
monotherapy; RR=1.04, 95% CI 0.85–1.28, P=0.705)
• Meta-analysis suggest that use of CAZ–AVI in monotherapy or combination
for infections due to CRE or CRPa could show a similar effect on mortality
and microbiological cure rates
Efficacy of CAZ–AVI in monotherapy or combination therapy against carbapenem-resistant
Gram-negative bacteria: a meta-analysis
Onorato L, et al. Int J Antimicrob Agents 2019;54(6):735–740
Study background
• Comprehensive computerised literature search was performed based on
CAZ–AVI monotherapy or combination therapy with other active agents for
infections due to CRE or CRPa
• Databases Medline, Google Scholar and the Cochrane Library
were searched
• Inclusion criteria characteristics were:
– Reported sufficient data to calculate RR and 95% CI
– Case-control studies, cohort studies or case series
– Full-text, in English
• Overall, 11 articles were included in the meta-analysis
Outcome No. of
studies
Combination
therapy
(events/total
%)
Monotherapy
(events/total
%)
Risk ration
(95% CI)
P-value Heterog
eneity
test (P-
value)
I2
Mortality (all patients) 11 77/202 (38.1) 60/194 (30.9) 1.18
(0.88-1.58)
0.259 0.987 0
%
Microbiological cure (all
patients)
7 61/94 (64.9) 97/153 (63.4) 1.04
(0.85-1.28)
0.705 0.883 0
%
Mortality (excluding
patients infected with
Pseudomonas )
9 74/191 (38.7) 58/186 (31.2) 1.20
(0.89-1.61)
0.229 0.923 0
%
Microbiological cure
(excluding patients
infected with
Pseudomonas )
6 57/90 (63.3) 91/147 (61.9) 1.05
(0.84-1.31)
0.653 0.687 0
%
CAZ–AVI, ceftazidime–avibactam; CRE, carbapenem-resistant
Enterobacteriaceae; CI, confidence intervals; CRPa, carbapenem-
resistant Pseudomonas aeruginosa;
RR, relative risk
Meta-analysis of clinical outcomes in the overall population
Adapted from Onorato, et al. 2019

29. Ceftazidime–avibactam compared to colistin
• Prospective multicenter cohort
• 137 patients with CRE infection1
o 38 received ceftazidime–avibactam first (monotherapy n=14 [37%])1
o 99 received colistin first (monotherapy n=6 [6%])1
• Baseline characteristics were similar
o Median Charlson comorbidity score 3 (IQR: 1–5)1
o Median Pitt bacteremia score 4 (IQR: 2–6)1
• Types of CRE infection included:
o Respiratory tract infection (n=30)1
o UTI (n=19)1
• Pathogens included: K. pneumoniae (n=133), Enterobacter spp. (n=4)1
BSI, bloodstream infection; CRE, carbapenem-resistant Enterobacteriaceae; IQR, interquartile range; UTI, urinary tract infection.
1. van Duin D, et al. Clin Infect Dis 2018;66:163–71.

30. Ceftazidime–avibactam compared to colistin
CAZ–AVI, ceftazidime–avibactam; CI, confidence interval; IPTW, inverse probability of treatment weighting.
1. van Duin D, et al. Clin Infect Dis 2018;66:163–71.
Ceftazidime–avibactam Colistin
Death rate evaluated at Day 30 after therapy1
3/38 (8%) in CAZ–AVI patients versus 33/99 (33%) in colistin group
difference 23%, P=0.001
At Day 301
+ 64% adjusted probability of a better prognosis with CAZ–AVI than colistin
(CI 95% 57–71%)
Clinical outcomes were better in the patients who were treated first with
ceftazidime-avibactam rather than colistin
The use of ceftazidime-avibactam was associated with improved clinical
outcomes, especially decreased all-cause hospital mortality rate and
improved benefit-risk outcomes.

31. Population
Pharmacokinetic
Modelling of
Ceftazidime and
Avibactam
in the Plasma and
Epithelial Lining
Fluid of Healthy
Volunteers
• Compartmental modelling analysis
• ELF penetration of both ceftazidime (52%) and
avibactam (42%) was greater than previously
calculated at plasma concentrations relevant for
efficacy (~ 8 mg/l for ceftazidime and ~ 1 mg/l for
avibactam)
• ELF exposures of both drugs exceeded levels
required for efficacy in plasma
Dimelow R et al. Population Pharmacokinetic Modelling of Ceftazidime and Avibactam in the Plasma and Epithelial Lining Fluid of Healthy Volunteers. Drugs in R&D (2018) 18:221–230

32. 1. Vena A, Giacobbe DR, Castaldo N, et al. Clinical Experience with Ceftazidime-Avibactam for the Treatment of Infections due to Multidrug-Resistant Gram-Negative Bacteria Other than Carbapenem-
Resistant Enterobacterales. Antibiotics (Basel). 2020;9(2):71; 2. Santevecchi BA, Smith TT, MacVane SH. Clinical experience with ceftazidime/avibactam for treatment of antibiotic-resistant organisms other than Klebsiella
pneumoniae. Int J Antimicrob Agents. 2018;51(4):629-635
Outcomes in patients with P.aeruginosa
Study, year Study characteristics Susceptibility to Caz-Avi Outcomes Comments
Vena, 2020, Italy,
Infections other
than CR
Enterobacterales 1
41 pts received 72 h of
ceftazidime-avibactam
for GNB
Nosocomial pneumonia
49%
P.aeruginosa in 33 pts (80.5%); all
MDR isolates
Combination therapy in 80% pts
(colistin,AG, carbapenems)
Clinical success
at the end of the
follow-up period
was 90.5%,
• No
genotyping
done
Santevecci, 2018
USA 2
Infections other
than
K.pneumoniae
10 pts received Caz-AVI;
46% had pneumonia;
Total 21 isolates.
8 isolates (38%) of P.aeruginosa;
60% polymicrobial; Median MIC
1.5mg/L
50% received targeted
combination therapy
Clinical success
was achieved in
70% (n = 7/10) of
patients.

33. Role of
ceftazidime-
avibactam
• One of the most important additions to the
armamentarium for GN infections
• One of the first antibiotics that targets OXA
and KPC
• Post market reports, reflecting real-life use
are very encouraging, in terms of safety,
clinical response, and survival
• Efficacy compared to colistin better with
64% probability of better outcome
• Early use has been associated with better
outcomes
Karaiskos I, Lagou S, Pontikis K, Rapti V, Poulakou G. The "Old" and the "New" Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How. Front Public Health. 2019 Jun 11;7:151.

34. Ceftazidime-avibactam & stewardship
• Use of ceftazidime/avibactam in clinical practice requires high levels of antimicrobial stewardship
• Stewardship teams are tasked with minimizing barriers to utilization, but must also be careful not to
promote overuse of these agents
• Minimizing barriers will ensure that these agents can be appropriately used when needed.
• Institutions with particularly high rates of CRE, testing of ceftazidime/avibactam susceptibility for
organisms identified as carbapenem-resistant should be considered to further reduce time to
susceptibility information
• Protecting the use of ceftazidime/avibactam will help mitigate development of resistance and maintain
their use as CRE active agents for as long as possible
• Development of criteria for use or a system of protected use is essential to make sure the antibiotic is
safeguarded
Bradley N, Lee Y. Practical Implications of New Antibiotic Agents for the Treatment of Carbapenem-Resistant Enterobacteriaceae. Microbiol Insights. 2019; 12: 1178636119840367.

40. Summary • Resistance among gram negative bacteria is on the
rise, especially for carbapenems
• Rise in the incidence of OXA-48 (either alone or in
combination with other beta lactamases such as
ESBLs)
• Rapid molecular tests will help direct appropriate
antimicrobial therapy
• Ceftazidime-avibactam has shown good efficacy in the
real world studies for carbapenem resistant
enterobacteriaceae and MDR P.aeruginosa
• It has resulted in better outcomes as compared to
colistin in CRE
• Early use is associated with better outcomes
• Good antimicrobial stewardship practices will be
required

41. Summary of Prescribing Information_Ceftazidime- Avibactam
Generic Name: Ceftazidime Pentahydrate and Avibactam Sodium Brand name: Zavicefta ™Trademark Proprietor: Pfizer Ireland Pharmaceuticals Indication: For the treatment of the following infections in adults
with Complicated intra-abdominal infection (cIAI), Complicated urinary tract infection (cUTI), including pyelonephritis, Hospital- acquired pneumonia (HAP), including ventilator associated pneumonia (VAP) with
susceptible gram negative microorganisms Pharmaceutical Form, Dosage and Method of Administration : Powder for concentrate for solution for infusion (powder for concentrate). A white to yellow powder.
Recommended intravenous dose for patients with estimated CrCL ≥51 mL/min: 2.5 gm every 8 hourly as a 2 hour infusion for 5-14 days in cIAI (To be used in combination with metronidazole when anaerobic
pathogens are known or suspected to be contributing to the infectious process), 5-10 days for cUTI with pyelonephritis & 7-14 days for HAP/VAP. To be used in combination with an antibacterial agent active
against Gram-positive pathogens when these are known or suspected to be contributing to the infectious process. For patients with cUTI including pyelonephritis, The total duration shown may include
intravenous Zavicefta followed by appropriate oral therapy. No dosage adjustment is required in elderly patients. No dosage adjustment is required in patients with mild renal impairment (estimated CrCL ≥51 -
≤80 mL/min). Dosage for Cr CL ≤ 51 mg/mL: 1g/0.25 g every 8 hours by 2 hour infusion for Cr CL 31-50 mL/min, 0.75g/0.1875g every 12 hours by 2 hr infusion for Cr CL 16-30mL/min, 0.75g/0.1875g every 24
hours by 2 hr infusion for Cr CL 6- 15mL/min and 0.75g/0.1875g every 48 hours by 2 h infusion for ESRD including on hemodialysis. Ceftazidime and avibactam are removed by haemodialysis. Dosing of Zavicefta
on haemodialysis days should occur after completion of haemodialysis.No dosage adjustment is required in patients with hepatic impairment. Safety and efficacy in children and adolescents below 18 years of age
have not yet been established. Zavicefta is administered by intravenous infusion over 120 minutes in an infusion volume of 100 mL. Contraindications : Hypersensitivity to the active substances or to any of the
excipients, hypersensitivity to any cephalosporin antibacterial agent & Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of β-lactam antibacterial agent (e.g. penicillins,
monobactams or carbapenems). Warnings and Precautions, including special population: Serious and occasionally fatal hypersensitivity reactions are possible. In case of hypersensitivity reactions, treatment with
Zavicefta must be discontinued immediately and adequate emergency measures must be initiated. Clostridium difficile-associated diarrhoea has been reported with ceftazidime/avibactam, and can range in
severity from mild to life-threatening. Discontinuation of therapy with Zavicefta and the administration of specific treatment for Clostridium difficile should be considered. Neurological sequelae, including tremor,
myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, have occasionally been reported with ceftazidime when the dose has not been reduced in patients with renal impairment. In
patients with renal impairment, close monitoring of estimated creatinine clearance is advised. Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as
aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function. Ceftazidime/avibactam use may cause development of a positive direct antiglobulin test (DAGT, or Coombs test), which
may interfere with the cross-matching of blood and/or may cause drug-induced immune hemolytic anemia. Patients experiencing anemia during or after treatment with Zavicefta should be investigated or this
possibility. Adverse Reactions: Very common- Coombs direct test positive; Common: Candidiasis (including Vulvovaginal candidiasis and Oral candidiasis), Eosinophilia, Thrombocytosis, Thrombocytopenia,
Headache, Dizziness, Diarrhoea; Abdominal pain; Nausea;Vomiting; Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood alkaline phosphatase increased; Gamma glutamyl
transferase increased;Blood lactate dehydrogenase increased, Rash maculo-papular; Urticaria; Pruritus; Infusion site thrombosis; Infusion site phlebitis; Pyrexia Drug Interactions: Co-administration of avibactam
with probenecid is not recommended as Probenecid (a potent OAT inhibitor) inhibits this uptake by 56% to 70% in vitro and, therefore, has the potential to alter the elimination of avibactam. Avibactam showed
no significant inhibition and avibactam & ceftazidime showed no induction (at clinically relevant concentrations) of CYP P450 enzymes in vitro. Avibactam and ceftazidime do not inhibit the major renal or hepatic
transporters in the clinically relevant exposure range, therefore the interaction potential via these mechanisms is considered to be low. There is no interaction between ceftazidime and avibactam, and between
ceftazidime/avibactam and metronidazole. Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may
adversely affect renal function. Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but due to the possibility of antagonism in vivo
this drug combination should be avoided. Overdose : Overdose with ceftazidime/avibactam can lead to neurological sequelae including encephalopathy, convulsions and coma, due to the ceftazidime component.
Serum levels of ceftazidime can be reduced by haemodialysis or peritoneal dialysis. During a 4-hour haemodialysis period, 55% of the avibactam dose was removed. Storage condition: Store below 30°C in the
original package. Protect from light. The reconstituted vial should be used immediately. After dilution, the chemical and physical in-use stability has been demonstrated for up to 24 hours at 2 - 8°C, followed by up
to 12 hours at not more than 25°C.
Adapted from Zavicefta. Local Product Document. Version LPDZAVIC032020. Please refer to the complete prescribing information for complete details Complete prescribing information available on request
Licensed user: Pfizer Limited, India