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TACKLING THE
MENACE OF MDR
GRAM NEGATIVE
INFECTIONS WITH
EARLY USE OF
NOVEL BL-BLI: CASE
FILES
Disclaimer
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PP-ZVA-IND-0673; 25th May 2022
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 8th Feb 2022.
The menace of gram negative organisms!
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 8th Feb 2022.
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)
1. EPIDEMIOLOGY &
2. SUSCEPTIBILITY TRENDS
IN RESPECTIVE HOSPITALS
FOR GRAM NEGATIVE
INFECTIONS
Points for discussion
CASE STUDY
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
WHAT WOULD BE THE NEXT
STEP?
1. START AN APPROPRIATE
ANTIBIOTIC
2. SEND CULTURE SAMPLES
3. ASSESS RISK FACTORS FOR
MDR
Points of discussion
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
Case contd • Patient started on vancomycin and meropenem
• 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
WHICH TESTS?
WHEN?
ADVANTAGE?
Points of discussion
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 (MATRIX
ASSISTED LASER DESORTPTION
INONIZATION – TIME OF FLIGHT
MASS SPECTRA)
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
Case contd • Culture results- Klebsiella pneumoniae
• On rapid molecular testing, OXA-48 detected
• Disc diffusion test shows susceptibility to ceftazidime
avibactam
Hypothetical scenario
Understanding
OXA- 48
(Oxacillinase Beta lactamase )
• 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
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%).
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
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
EPIDEMIOLOGY OF
BETA LACTAMASES AT
RESPECTIVE
HOSPITALS
Points of discussion
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
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, MartĂ­nez LM, Calbo E, Garau J. Update on the role of ceftazidime-avibactam in the management of carbapenemase-producing Enterobacterales. Future Microbiol. 2020;15:473-
Avibactam has a broad spectrum of activity2
1. Zhanel GG, Lawson CD, Adam H, Schweizer F, Zelenitsky S, LagacÊ-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, PÊchereau 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.
Ceftazidime - avibactam spectrum of activity
VAP, ventilator-associated pneumonia.
Zavicefta (Ceftazidime-Avibactam). Local product document. LPDZAV022021
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.
EVIDENCE FOR
EFFICACY &
SAFETY
• 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
• 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
• 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
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.
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.
Early use
was
associated
with
improved
outcomes
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).
Study by Jorgensen et al
and
STUDY byTEMKIN et al
1. Bonine NG, et al. Impact of Delayed Appropriate Antibiotic Therapy on Patient Outcomes by Antibiotic Resistance Status from Serious Gram-negative Bacterial Infections. Am J Med Sci. 2019;357(2):103-11
† Defined as no receipt of antibiotic(s) with relevant microbiological activity on or
within 2 days of index date. ‡ Compared with receipt of timely appropriate therapy.
Study by Jorgensen et al: Real-World Experience With Ceftazidime-Avibactam for
Multidrug-Resistant Gram-Negative Bacterial Infections
• Multicenter, retrospective, observational cohort study conducted at 6 centers in the United States between
2015 and 2019
• 203 patients included:
1. were ≥18 years of age,
2. received ≥72 hours of CZA therapy
• 57.6% with hospital-acquired infections
– 50.2% (n=102) patients with a high severity of illness at infection onset residing in the ICU and a median
SOFA score of 5 (IQR, 2–8)
• 57.6% Carbapenem-resistant Enterobatceriaceae.
– 63.2% K pneumoniae
– 14.5% Escherichia coli
– 12.8% Enterobacter Spp.
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).
Study by Jorgensen et al: Real-World Experience With Ceftazidime-Avibactam for
Multidrug-Resistant Gram-Negative Bacterial Infections
• Primary outcome:
– Clinical failure defined as a composite of
30-day all-cause mortality, 30-day microbiological failure, and/or failure to resolve or improve signs or symptoms of
infection on CZA-AVI
• Study Results:
– Early use of CZA (within 48 hours of infection onset), was associated with improved clinical outcomes in all indications
including bacteraemia
– 30-day mortality rate at 17.2% and recurrence rates at 6%
– 71% Overall clinical success rate*
– Therapy resistance was not detected
– Underscores the important role of rapid diagnostic testing for early pathogen identification and susceptibility testing
Jorgensen SCJ, Trinh TD, Zasowski EJ et al. Real-world experience with ceftazidime-avibactam for multidrug-resistantgram-negative bacterial infections. Open Forum Infect. Dis. 6(12), ofz522 (2019).
*Jorgensen SCJ, et al. Real-world experience with Ceftazidime-Avibactam formultidrug-resistant gram-negative bacterial infections. Open Forum Infect Dis. 2019;6(12):ofz522. (SupplementaryAppendix).
STUDY by TEMKIN ET al: 2017
• 38 patients included: Minimum length of treatment with compassionate use CAZ-AVI was 3 days
– 63.2% (n=24) were given the standard dose of CAZ-AVI throughout their treatment (2 g ceftazidime– 0.5 g avibactam
every 8 h)
– 14 patients with renal impairment received adjusted doses.
• Antibiotics before CAZ-AVI
– Received antibiotics before CAZ-AVI for this infection: 36 (94.7)
– Days of antibiotic treatment before CAZ-AVI, median (IQR): 13 (7–31)
– No. of antibiotics before CAZ-AVI, median (IQR): 3 (3–4)
• 34 patients infected with Klebsiella pneumoniae
– 1 with Klebsiella oxytoca
– 1 with Escherichia coli
– 2 with P. aeruginosa
• 89.5% (n=34) hospital-acquired infections
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
Study Design:
STUDY by TEMKIN ET al: 2017
– 79% of patients with negative cultures at the end of treatment survived until discharge
– 73% of patients achieved microbiological cure
– 39.5%All-cause in-hospital mortality
– 24% 30 day all-cause mortality
– 59% Overall clinical success rate
– ‘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’
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
Primary Outcomes
 Clinical cure at the end of treatment
 Microbiological cure at the end of treatment
 All-cause in-hospital mortality
Study Results:
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
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.
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.
INFECTIOUS DISEASES SOCIETY OF
AMERICA (IDSA) ANTIMICROBIAL
RESISTANT TREATMENT GUIDANCE:
GRAM-NEGATIVE BACTERIAL INFECTIONS
A Focus on Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E),
Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-
Treat Resistance (DTR-P. aeruginosa
Please refer to the complete guideline for more information
General
recommendations
• Preferred and alternative treatment
recommendations in this guidance
document assume that the causative
organism has been identified and in
vitro activity of antibiotics has been
demonstrated
• Empiric treatment recommendations
are not provided
• Recommendations on duration of
therapy are not mentioned
Tamma P et al. Infectious Diseases Society of America Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. A Focus on Extended-
Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat
Resistance (DTR-P. aeruginosa). Published by IDSA. Published on 8 Sept 2020. Available at https://www.idsociety.org/practice-guideline/amr-guidance/.
Accessed on 8th Feb 2022
Knowledge of whether a
CRE clinical isolate is
carbapenemase-producing
and, if it is, the specific
carbapenemase produced
is important in guiding
treatment decisions
Tamma P et al. Infectious Diseases Society of America Guidance on the Treatment of Antimicrobial Resistant Gram-Negative
Infections. A Focus on Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant
Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Published by IDSA.
Published on 8 Sept 2020. Available at https://www.idsociety.org/practice-guideline/amr-guidance/. Accessed on 8th Feb 2022
Recommended antibiotic
treatment options for
carbapenem-resistant
Enterobacterales (CRE),
assuming in vitro
susceptibility to agents
Source of infection Preferred treatment Alternative treatment
Pyelonephritis or cUTI Ceftazidime-avibactam,
meropenem-vaborbactam,
imipenem-cilastatin-
relebactam, and cefiderocol
Once-daily aminoglycosides
Infections outside of the
urinary tract
Resistant to ertapenem,
meropenem, AND
carbapenemase testing
results are either not
available or negative
Ceftazidime-avibactam*,
meropenem-vaborbactam,
and imipenem-cilastatin-
relebactam
Cefiderocol
Tigecycline, eravacycline
(uncomplicated intra-
abdominal infections only)
OXA-48-like
carbapenemase identified
Ceftazidime-avibactam* Cefiderocol
Tigecycline, eravacycline
(uncomplicated intra-
abdominal infections only)
*Ceftazidime-avibactam is approved in adults for treatment of cIAI, cUTI including pyelonephritis and HAP-VAP with susceptible gram
negative organisms
Tamma P et al. Infectious Diseases Society of America Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. A Focus on Extended-Spectrum β-
lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P.
aeruginosa). Published by IDSA. Published on 8 Sept 2020. Available at https://www.idsociety.org/practice-guideline/amr-guidance/. Accessed on 8th Feb 2022
Recommended antibiotic
treatment options for
difficult-to-treat (DTR)
Pseudomonas aeruginosa,
assuming in vitro
susceptibility to agents
Source of
infection
Preferred treatment Alternative
treatment
Pyelonephritis or
cUTI
Ceftolozane-tazobactam,
ceftazidime-avibactam,
imipenem-cilastatin-
relebactam, and cefiderocol
Once-daily
aminoglycosides
Infections outside
of the urinary
tract
Ceftolozane-tazobactam,
ceftazidime-avibactam*, or
imipenem-cilastatin-
relebactam
Cefiderocol
Aminoglycoside
monotherapy: limited
to uncomplicated
bloodstream
infections with
complete source
control
Tamma P et al. Infectious Diseases Society of America Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. A Focus on
Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with
Difficult-to-Treat Resistance (DTR-P. aeruginosa). Published by IDSA. Published on 8 Sept 2020. Available at https://www.idsociety.org/practice-
guideline/amr-guidance/. Accessed on 8th Feb 2022
*Ceftazidime-avibactam is approved in adults for treatment of cIAI, cUTI including pyelonephritis and HAP-VAP with susceptible gram
negative organisms
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.
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
Case 1* • 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
* This is a hypothetical case
WHAT WOULD BE THE NEXT
STEP?
1. START AN APPROPRIATE
ANTIBIOTIC
2. SEND CULTURE SAMPLES
3. ASSESS RISK FACTORS FOR
MDR
Points of discussion
Case contd • Patient started on vancomycin and meropenem
• 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
WHICH TESTS?
WHEN?
ADVANTAGE?
Points of discussion
Case contd • Culture results- Klebsiella pneumoniae
• On rapid molecular testing, OXA-48 detected
• Ceftazidime-Avibactam therapy initiated
May indicate
ESBL production
Case 2*
• 76 y M patient
• CAD, PTCA in 2013, hypothyroid
• PLWH (virologically suppressed, onTDF/FTC/EFV)
• 17/8/19-Admitted with AcuteAWMI with in stent stenosis of
RCA stent- plan CABG
• Preop- Hb- 8.4,TC- 9670, PC- 2.79 lac, Creatinine- 3.1
• 20/8/19-CABG done- extubated on POD 1
• 24/8- Drowsy, cough with expectoration ? LVF
• Sputum C/S sent- Klebsiella pneumoniae (CR)
• Genotyping sent
* This is a hypothetical case
• 30/8- Fever,TC- 22050
• New opacities in CXR, leucocytosis,
BIPAP, drowsy
• ID Reference
• (Old) sputum C/S- Kleb pneumoniae
• No new respiratory culture available
• Blood C/S negative
Fosfomycin S , Colistin MIC <0.5
Carba R Gene Xpert
CAZ/AVI – Sensitive (MIC 2 mcg/ml)
Rxed- 10 days of monotherapy with Ceftazidime/avibactam
Patient discharged on day 12 of therapy
• Study Name : Novel β-lactam/β-lactamase inhibitor combinations versus
alternative antibiotics in adults with hospital-acquired pneumonia or
ventilator-associated pneumonia: an integrated analysis of three
randomised controlled trial.
This study was published in Journalo f global antibitimicobial resistance
in 2021.
Pubmed, web of science, the cochrane library, ovid MEDLINE, embase
and EBSCO databases were searched for randomised controlled trials
(RCTs) published before 13 september 2020.
Only RCTs comparing the treatment efficacy of novel BL/BLI
combinations with other antibiotics for HAP/VAP in adult patients were
included in this integrated analysis.
PROVEN EFFICACY FOR BL- BLI COMBINATION: Some latest research
• Early administration of appropriate antibiotics is key for managing
patients with HAP/VAP.
• The presence of multidrug-resistant organisms (MDROs), such as
carbapenem-resistant Pseudomonas aeruginosa, extended-spectrum
β-lactamase (ESBL)-producing Enterobacteriaceae and multidrug-
resistant Acinetobacter baumannii, is a major factor associated with
the selection of inappropriate antibiotic treatment.
• To overcome the threat of MDROs, new antibiotics with broad-
spectrum activity are urgently required, particularly for use against
antibiotic-resistant bacteria.
• Recently, several novel β-lactam/β-lactamase inhibitor (BL/BLI)
combinations, including ceftolozane/tazobactam, ceftazidime/avibactam,
meropenem/vaborbactam and imipenem/cilastatin/relebactam, have been
assessed in largescale randomised controlled trials (RCTs) for clinical use,
such as in cases of complicated intra-abdominal infection (cIAI),
complicated urinary tract infection (cUTI) and HAP/VAP.
• Moreover, several meta-analyses have provided evidence regarding their
efficacy and safety for clinical treatment of cIAIs and cUTIs.
• However, evidence regarding the efficacy and safety of novel BL/BLI
combinations in HAP/VAP treatment is lacking.
• This study provided new evidence for the efficacy and safety of these
BL/BLI combinations in the treatment of adult patients with HAP/VAP
• All three RCTs included were phase 3, multicentre and multinational
studies.
• Each study investigated one of the following novel BL/BLI
combinations : imipenem/cilastatin/relebactam;
ceftazidime/avibactam; and ceftolozane/tazobactam.
• The comparative agents were meropenem in two studies and
piperacillin/tazobactam in one study.
Results: Three RCTs were included and no significant difference in
clinical cure rate of test of cure was observed between the novel
BL/BLI combinations and comparators [odds ratio (OR) = 1.01, 95%
confidence interval (CI) 0.81–1.27; i 2 = 35%].
The 28-day all-cause mortality was 16.2% and 17.6% for patients
receiving novel BL/BLI combinations and comparators, respectively,
and no significant difference was noted (OR = 0.90, 95% ci 0.69–1.16;
i 2 = 11%).
Compared with comparators, novel BL/BLI combinations were
associated with a similar microbiological response (OR = 1.06, 95% ci
0.73–1.54; I 2 = 64%) and a similar risk of adverse events (AES)
[treatment-emergent AES: OR = 1.04, 95% ci 0.83–1.30; I 2 = 0%;
serious AES: OR = 1.14,

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Tacking the menage of gram negative inf with novel bl bli.pptx

  • 1. TACKLING THE MENACE OF MDR GRAM NEGATIVE INFECTIONS WITH EARLY USE OF NOVEL BL-BLI: CASE FILES
  • 2. Disclaimer Pfizer Limited The Capital – A Wing-1802, 18th floor, Plot No. C-70, G Block, Bandra Kurla Complex, Bandra (East), Mumbai 400051 For the use only of Registered Medical Practitioners or a Hospital or a Laboratory General disclaimer for the presentation “The Content in this presentation is only intended for healthcare professionals in India. The medical information in this presentation is provided as an information resource only, and is not to be used or relied on for any diagnostic or treatment purpose.” Additional slide by the Speaker “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.” See Summary of Prescribing Information on last page​ Full Prescribing Information available on request​ PP-ZVA-IND-0673; 25th May 2022
  • 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 8th Feb 2022. 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 8th Feb 2022. 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
  • 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. 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
  • 10. Case contd • Patient started on vancomycin and meropenem • 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
  • 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 (MATRIX ASSISTED LASER DESORTPTION INONIZATION – TIME OF FLIGHT MASS SPECTRA) 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 (Oxacillinase Beta lactamase ) • 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. 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
  • 18. EPIDEMIOLOGY OF BETA LACTAMASES AT RESPECTIVE HOSPITALS Points of discussion
  • 19. 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
  • 20. 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, MartĂ­nez LM, Calbo E, Garau J. Update on the role of ceftazidime-avibactam in the management of carbapenemase-producing Enterobacterales. Future Microbiol. 2020;15:473-
  • 21. Avibactam has a broad spectrum of activity2 1. Zhanel GG, Lawson CD, Adam H, Schweizer F, Zelenitsky S, LagacĂŠ-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, PĂŠchereau 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. LagacĂŠ-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.
  • 22. Ceftazidime - avibactam spectrum of activity VAP, ventilator-associated pneumonia. Zavicefta (Ceftazidime-Avibactam). Local product document. LPDZAV022021 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. • 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
  • 25. • 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
  • 26. • 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
  • 27. 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.
  • 28. 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.
  • 29. Early use was associated with improved outcomes 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). Study by Jorgensen et al and STUDY byTEMKIN et al
  • 30. 1. Bonine NG, et al. Impact of Delayed Appropriate Antibiotic Therapy on Patient Outcomes by Antibiotic Resistance Status from Serious Gram-negative Bacterial Infections. Am J Med Sci. 2019;357(2):103-11 † Defined as no receipt of antibiotic(s) with relevant microbiological activity on or within 2 days of index date. ‡ Compared with receipt of timely appropriate therapy.
  • 31. Study by Jorgensen et al: Real-World Experience With Ceftazidime-Avibactam for Multidrug-Resistant Gram-Negative Bacterial Infections • Multicenter, retrospective, observational cohort study conducted at 6 centers in the United States between 2015 and 2019 • 203 patients included: 1. were ≥18 years of age, 2. received ≥72 hours of CZA therapy • 57.6% with hospital-acquired infections – 50.2% (n=102) patients with a high severity of illness at infection onset residing in the ICU and a median SOFA score of 5 (IQR, 2–8) • 57.6% Carbapenem-resistant Enterobatceriaceae. – 63.2% K pneumoniae – 14.5% Escherichia coli – 12.8% Enterobacter Spp. 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).
  • 32. Study by Jorgensen et al: Real-World Experience With Ceftazidime-Avibactam for Multidrug-Resistant Gram-Negative Bacterial Infections • Primary outcome: – Clinical failure defined as a composite of 30-day all-cause mortality, 30-day microbiological failure, and/or failure to resolve or improve signs or symptoms of infection on CZA-AVI • Study Results: – Early use of CZA (within 48 hours of infection onset), was associated with improved clinical outcomes in all indications including bacteraemia – 30-day mortality rate at 17.2% and recurrence rates at 6% – 71% Overall clinical success rate* – Therapy resistance was not detected – Underscores the important role of rapid diagnostic testing for early pathogen identification and susceptibility testing Jorgensen SCJ, Trinh TD, Zasowski EJ et al. Real-world experience with ceftazidime-avibactam for multidrug-resistantgram-negative bacterial infections. Open Forum Infect. Dis. 6(12), ofz522 (2019). *Jorgensen SCJ, et al. Real-world experience with Ceftazidime-Avibactam formultidrug-resistant gram-negative bacterial infections. Open Forum Infect Dis. 2019;6(12):ofz522. (SupplementaryAppendix).
  • 33. STUDY by TEMKIN ET al: 2017 • 38 patients included: Minimum length of treatment with compassionate use CAZ-AVI was 3 days – 63.2% (n=24) were given the standard dose of CAZ-AVI throughout their treatment (2 g ceftazidime– 0.5 g avibactam every 8 h) – 14 patients with renal impairment received adjusted doses. • Antibiotics before CAZ-AVI – Received antibiotics before CAZ-AVI for this infection: 36 (94.7) – Days of antibiotic treatment before CAZ-AVI, median (IQR): 13 (7–31) – No. of antibiotics before CAZ-AVI, median (IQR): 3 (3–4) • 34 patients infected with Klebsiella pneumoniae – 1 with Klebsiella oxytoca – 1 with Escherichia coli – 2 with P. aeruginosa • 89.5% (n=34) hospital-acquired infections 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 Study Design:
  • 34. STUDY by TEMKIN ET al: 2017 – 79% of patients with negative cultures at the end of treatment survived until discharge – 73% of patients achieved microbiological cure – 39.5%All-cause in-hospital mortality – 24% 30 day all-cause mortality – 59% Overall clinical success rate – ‘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’ 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 Primary Outcomes  Clinical cure at the end of treatment  Microbiological cure at the end of treatment  All-cause in-hospital mortality Study Results:
  • 35. 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
  • 36. 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.
  • 37. 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.
  • 38. INFECTIOUS DISEASES SOCIETY OF AMERICA (IDSA) ANTIMICROBIAL RESISTANT TREATMENT GUIDANCE: GRAM-NEGATIVE BACTERIAL INFECTIONS A Focus on Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to- Treat Resistance (DTR-P. aeruginosa Please refer to the complete guideline for more information
  • 39. General recommendations • Preferred and alternative treatment recommendations in this guidance document assume that the causative organism has been identified and in vitro activity of antibiotics has been demonstrated • Empiric treatment recommendations are not provided • Recommendations on duration of therapy are not mentioned Tamma P et al. Infectious Diseases Society of America Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. A Focus on Extended- Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Published by IDSA. Published on 8 Sept 2020. Available at https://www.idsociety.org/practice-guideline/amr-guidance/. Accessed on 8th Feb 2022
  • 40. Knowledge of whether a CRE clinical isolate is carbapenemase-producing and, if it is, the specific carbapenemase produced is important in guiding treatment decisions Tamma P et al. Infectious Diseases Society of America Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. A Focus on Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Published by IDSA. Published on 8 Sept 2020. Available at https://www.idsociety.org/practice-guideline/amr-guidance/. Accessed on 8th Feb 2022
  • 41. Recommended antibiotic treatment options for carbapenem-resistant Enterobacterales (CRE), assuming in vitro susceptibility to agents Source of infection Preferred treatment Alternative treatment Pyelonephritis or cUTI Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin- relebactam, and cefiderocol Once-daily aminoglycosides Infections outside of the urinary tract Resistant to ertapenem, meropenem, AND carbapenemase testing results are either not available or negative Ceftazidime-avibactam*, meropenem-vaborbactam, and imipenem-cilastatin- relebactam Cefiderocol Tigecycline, eravacycline (uncomplicated intra- abdominal infections only) OXA-48-like carbapenemase identified Ceftazidime-avibactam* Cefiderocol Tigecycline, eravacycline (uncomplicated intra- abdominal infections only) *Ceftazidime-avibactam is approved in adults for treatment of cIAI, cUTI including pyelonephritis and HAP-VAP with susceptible gram negative organisms Tamma P et al. Infectious Diseases Society of America Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. A Focus on Extended-Spectrum β- lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Published by IDSA. Published on 8 Sept 2020. Available at https://www.idsociety.org/practice-guideline/amr-guidance/. Accessed on 8th Feb 2022
  • 42. Recommended antibiotic treatment options for difficult-to-treat (DTR) Pseudomonas aeruginosa, assuming in vitro susceptibility to agents Source of infection Preferred treatment Alternative treatment Pyelonephritis or cUTI Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin- relebactam, and cefiderocol Once-daily aminoglycosides Infections outside of the urinary tract Ceftolozane-tazobactam, ceftazidime-avibactam*, or imipenem-cilastatin- relebactam Cefiderocol Aminoglycoside monotherapy: limited to uncomplicated bloodstream infections with complete source control Tamma P et al. Infectious Diseases Society of America Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. A Focus on Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Published by IDSA. Published on 8 Sept 2020. Available at https://www.idsociety.org/practice- guideline/amr-guidance/. Accessed on 8th Feb 2022 *Ceftazidime-avibactam is approved in adults for treatment of cIAI, cUTI including pyelonephritis and HAP-VAP with susceptible gram negative organisms
  • 43. 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.
  • 44. 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
  • 45. Case 1* • 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 * This is a hypothetical case
  • 46. WHAT WOULD BE THE NEXT STEP? 1. START AN APPROPRIATE ANTIBIOTIC 2. SEND CULTURE SAMPLES 3. ASSESS RISK FACTORS FOR MDR Points of discussion
  • 47. Case contd • Patient started on vancomycin and meropenem • 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
  • 49. Case contd • Culture results- Klebsiella pneumoniae • On rapid molecular testing, OXA-48 detected • Ceftazidime-Avibactam therapy initiated May indicate ESBL production
  • 50. Case 2* • 76 y M patient • CAD, PTCA in 2013, hypothyroid • PLWH (virologically suppressed, onTDF/FTC/EFV) • 17/8/19-Admitted with AcuteAWMI with in stent stenosis of RCA stent- plan CABG • Preop- Hb- 8.4,TC- 9670, PC- 2.79 lac, Creatinine- 3.1 • 20/8/19-CABG done- extubated on POD 1 • 24/8- Drowsy, cough with expectoration ? LVF • Sputum C/S sent- Klebsiella pneumoniae (CR) • Genotyping sent * This is a hypothetical case
  • 51. • 30/8- Fever,TC- 22050 • New opacities in CXR, leucocytosis, BIPAP, drowsy • ID Reference • (Old) sputum C/S- Kleb pneumoniae • No new respiratory culture available • Blood C/S negative
  • 52. Fosfomycin S , Colistin MIC <0.5
  • 53. Carba R Gene Xpert
  • 54. CAZ/AVI – Sensitive (MIC 2 mcg/ml) Rxed- 10 days of monotherapy with Ceftazidime/avibactam Patient discharged on day 12 of therapy
  • 55. • Study Name : Novel β-lactam/β-lactamase inhibitor combinations versus alternative antibiotics in adults with hospital-acquired pneumonia or ventilator-associated pneumonia: an integrated analysis of three randomised controlled trial. This study was published in Journalo f global antibitimicobial resistance in 2021. Pubmed, web of science, the cochrane library, ovid MEDLINE, embase and EBSCO databases were searched for randomised controlled trials (RCTs) published before 13 september 2020. Only RCTs comparing the treatment efficacy of novel BL/BLI combinations with other antibiotics for HAP/VAP in adult patients were included in this integrated analysis. PROVEN EFFICACY FOR BL- BLI COMBINATION: Some latest research
  • 56. • Early administration of appropriate antibiotics is key for managing patients with HAP/VAP. • The presence of multidrug-resistant organisms (MDROs), such as carbapenem-resistant Pseudomonas aeruginosa, extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and multidrug- resistant Acinetobacter baumannii, is a major factor associated with the selection of inappropriate antibiotic treatment. • To overcome the threat of MDROs, new antibiotics with broad- spectrum activity are urgently required, particularly for use against antibiotic-resistant bacteria.
  • 57. • Recently, several novel β-lactam/β-lactamase inhibitor (BL/BLI) combinations, including ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam and imipenem/cilastatin/relebactam, have been assessed in largescale randomised controlled trials (RCTs) for clinical use, such as in cases of complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI) and HAP/VAP. • Moreover, several meta-analyses have provided evidence regarding their efficacy and safety for clinical treatment of cIAIs and cUTIs. • However, evidence regarding the efficacy and safety of novel BL/BLI combinations in HAP/VAP treatment is lacking. • This study provided new evidence for the efficacy and safety of these BL/BLI combinations in the treatment of adult patients with HAP/VAP
  • 58. • All three RCTs included were phase 3, multicentre and multinational studies. • Each study investigated one of the following novel BL/BLI combinations : imipenem/cilastatin/relebactam; ceftazidime/avibactam; and ceftolozane/tazobactam. • The comparative agents were meropenem in two studies and piperacillin/tazobactam in one study.
  • 59.
  • 60.
  • 61. Results: Three RCTs were included and no significant difference in clinical cure rate of test of cure was observed between the novel BL/BLI combinations and comparators [odds ratio (OR) = 1.01, 95% confidence interval (CI) 0.81–1.27; i 2 = 35%]. The 28-day all-cause mortality was 16.2% and 17.6% for patients receiving novel BL/BLI combinations and comparators, respectively, and no significant difference was noted (OR = 0.90, 95% ci 0.69–1.16; i 2 = 11%). Compared with comparators, novel BL/BLI combinations were associated with a similar microbiological response (OR = 1.06, 95% ci 0.73–1.54; I 2 = 64%) and a similar risk of adverse events (AES) [treatment-emergent AES: OR = 1.04, 95% ci 0.83–1.30; I 2 = 0%; serious AES: OR = 1.14,

Editor's Notes

  1. The menace of gram negative organisms
  2. 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 8th Feb 2022.
  3. 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
  4. Hypothetical scenario
  5. 387 isolates (214 K. pneumoniae, 173 EC) tested, 93 (24.03%) were found to be CRE Of these, 71 (76.3%) were positive for at least one tested carbapenemase gene frequency of carbapenemase genes was 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%).
  6. .
  7. ESBL production
  8. 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
  9. Karlowsky KA 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. 2018;62(7):e02569-17. Kazmierczak KM et al. In vitro activity of ceftazidime/avibactam against isolates of Pseudomonas aeruginosa collected in European countries: INFORM global surveillance 2012-15. J Antimicrob Chemother. 2018;73(10):2777-2781
  10. For internal use only
  11. Bradley N, Lee Y. Practical Implications of New Antibiotic Agents for the Treatment of Carbapenem-Resistant Enterobacteriaceae. Microbiol Insights. 2019; 12: 1178636119840367.
  12. ESBL production