New and Emerging Antibiotics: Data and Practical Recommendations Focusing on beta-lactams and beta-lactamase inhibitors Robert A. Bonomo, M.D. Medical Service, Louis Stokes Cleveland VAMC Department of Medicine and Molecular Biology and Microbiology Case VA CARES Cleveland GRECC
DISCLOSURES and Appreciation Dr. Bonomo reports receiving research grants from NIH, VA, Achaogen, Allecra Therapeutics, Entasis Pharma, Merck & Co., Inc., Roche, Wockhardt, and Shionogi, Inc. Dr. Bonomo will not include discussion of unapproved or investigational uses of products or devices. Drs. Kriztina Papp-Wallace, Melissa Shelton Barnes, Focco van den Akker, Michael Jacobs, Phil Rather and Mr. Christopher Bethel
By 2050, increases in antimicrobial resistance (AMR) will be responsible for 300 million deaths Total GDP Loss 100.2 Trillion USD Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. Retrieved from http://amr-review.org/2014.
Why are we here?
PNAS 2018 Between 2000-2015, atb consumption increased 65% (21.1 34.8 billion DDDs), and the atb consumption rate increased 39% (11.3 15.7 DDDs per 1,000 inhabitants per day). The increase was driven by LMICs, where rising consumption was correlated w GDP/per capita growth (P = 0.004) Glycylcyclines, oxazolidinones, carbapenems, and polymyxins. It is getting more difficult to control consumption?
β-lactamases: major threat in Gram negative bacteria Clin. Microbiol. Rev. 2010, 23(1):160
Inky darkness and horror no longer can imipenem save your life. And then.the carbapenemases KPC-2 NDM-1 VIM-2 OXA-48
Each year approximately 1000+ deaths occur from CRE (Klebsiella and E. coli) 26% 44% of deaths in 7 studies were attributable to carbapenem resisistance Poor outcomes; Patel et al., observed a mortality rate of 40-50% in patients with BSI caused by CRKp. WHO estimates that the death rate from Ebola Virus infection is 50-60% (WHO estimates).
Cezanne Need to embark upon a journey of discovery
Recent Treatment Approaches
Inhibit b-lactamases: a major clinical achievement! First generation O H N O COOH OH O HOS O N COOH O H N O S O COOH N N N Clavulanic Acid Sulbactam Tazobactam Olivanic acid Sulfones
Second Generation
Preserving the b-lactam Promise the new generations Ceftazidime Avibactam Imipenem Relebactam Meropenem Vaborbactam
Cefepime Zidebactam VNRX-5133 AAI101 Sulbactam ETX-2514
Why was Avibactam so important? Reversible mode of action; first DBO Approved by FDA ( rushed:) for use in combination with ceftazidime (ceftazidime-avibactam) in treatment of complicated intra-abdominal and urinary tract infections Active against most class A and C and some class D β-lactamases Evolving information on resistance or mechanism of action Ehmann, D.E., et. al. J. Biol. Chem. 2013, 288(39), 27960-27971. Ehmann, D.E., et. al. PNAS, 2012, 109(29), 11663-11668. Lahiri. S., et. al., Antimicrob. Agents and Chemother. 2014, 58(10), 5704-5713.
Ceftazidime Avibactam Resembles portions of the cephem bicyclic ring system, Against Kp, the addition of AVI improves the activity of taz (~fourfold MIC reduction).
Does a better drug truly make a difference? The controversies Colistin vs. ceftazidime avibactam in the treatment of Infections due to Carbapenem-resistant Enterobacteriacea David van Duin, et al Clin Infect Dis. 2018 Jan 6;66(2):163-171 CID 2018
CRACKLE-I 137 patients met criteria; 38 patients were treated first with ceftazidime-avibactam and 99 with colistin. BSI (n=63, 46%) > PNA(n=30, 22%). No isolates had bla NDM, bla VIM, bla IMP or bla OXA- 48. ST258A (18/54, 33%) and ST258B (23/54, 43%) were the most commonly encountered clades of CRKP Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), a prospective, multicenter, observational study.
Conclusions In patients treated with TAZ AVI vs. colistin all-cause hospital mortality at 30-days after starting treatment was 9% vs 32% Thus..In this prospective, observational, multi-center cohort, all-cause propensity adjusted mortality was decreased in patients with CRE infections started on ceftazidime/avibactam vs. colistin (absolute risk reduction 23% [95% CI 9%-35%], p=0.0012).
Colistin group; n=99 n=13 n=25 n=30 n=41 One good drug is better than two bad ones C-A group; n=38 Are there concerns?
Emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections in Pittsburgh 37 consecutive patients treated with ceftazidime-avibactam >2 days Monotherapy 70% (26/37) Initial ceftazidime/avibactam MIC 50 = 1 μg/ml (range, 0.25 4) 31 K. pneumoniae: 12 KPC-2 and 16 KPC-3, all ST258 No NDM, VIM, IMP, or OXA-48 CTX-M (n = 7), OXA-1 (n = 4), SHV (n = 1), AmpC (n = 1) Cure in 59% (22/37); 75% cure with bloodstream infection Mortality 24% (9/37) (similar mono vs. combo); renal failure 10% Microbiological failure 27% (10/37) (recurrence/colonization) C/A MIC > 8 μg/ ml in 3 microbiologic failures (10-19 days) Shields RK et al. Clin Infect Dis 2016: 63; 12
Emergence of ceftazidime-avibactam resistance due to plasmid-borne bla KPC-3 mutations during treatment of carbapenem-resistant K. pneumoniae infections 3 cases without epidemiologic links Note: restored meropenem susceptibility Whole genome sequencing : mutations in bla KPC-3 (D179Y, T243M-A, V240G) Shields RK et al. Antimicrob. Agents Chemother. 2017;61:e02097-16 Papp Wallace KM, et al. Antimicrob Agents Chemother 2015; 59:3710 7
High rates of nonsusceptibility to ceftazidime-avibactam and New Delhi Metallo-β-lactamase producing Enterobacteriaceae at MD Anderson Cancer Center in Houston Since February 2015, Etest or KB for C/A in all meropenem resistant enterobacteria causing bloodstream infection PCR: bla IMP, bla VIM, bla KPC, bla OXA-48, bla SME, bla IMI/NMC-A, bla GES, bla NDM 432 enterobacteria isolates causing bloodstream infection 11 (2.5%) carbapenem-resistant: 7 (64%) C/A resistant, 5 different species 6 (55%) NDM+ : 1 with KPC-17 and NDM-1 1 C/A R without carbapenemases 4 C/A S : 2 with KPC-2, 2 without carbapenemases Important: Should not assume KPC genotype KPC nor ceftazidimeavibactam susceptibility in carbapenem-resistant enterobacteria Aitken S et al. Clin Infec Dis 2016:63
Meropenem-vaborbactam Structure Class and spectrum Carbapenem + vaborbactam- a novel boronic acid non-β-lactam β-lactamase inhibitor Administered 2 g + 2 g infused over 3 hours Potent inhibitor of KPC Does NOT inhibit OXA-48 or metallo-βlactamases Has same activity than meropenem against P. aeruginosa Clinical development: Approved by FDA 8/18
Activity of meropenem-vaborbactam against Enterobacteriaceae Organism group (no. of isolates tested) and antimicrobial agent KPC producers (135) Meropenem Meropenemvaborbactam OXA-48-likeproducers (25) Meropenem MBL producers (41) Meropenem Meropenemvaborbactam Meropenemvaborbactam Carbapenemasenegative (63) No. of isolates (cumulative %) MIC (μg/ml) of: 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 >32 35 (25.9) 19 (40.0) 7 (45.2) 19 (59.3) 24 (77.0) 19 (91.1) 2 (8.0) 1 (4.0) 7 (96.3) 1 (0.7) 0 (8.0) 0 (4.0) 2 (4.9) 1 (2.4) 3 (98.5) 6 (5.2) 0 (8.0) 1 (8.0) 4 (14.6) 5 (14.6) 1 (99.3) 11 (13.3) 3 (20.0) 2 (16.0) 5 (26.8) 6 (29.3) 1 (100.0) 10 (20.7) 5 (40.0) 5 (36.0) 5 (39.0) 4 (39.0) 21 (36.3) 5 (60.0) 5 (56.0) 2 (43.9) 2 (43.9) 16 (48.1) 5 (80.0) 6 (80.0) 8 (63.4) 5 (56.1) 70 (100.0) 5 (100.0) 5 (100.0) 15 (100.0) 18 (100.0) Meropenemvaborbactam 1 (1.6) 1 (3.2) 0 (3.2) 2 (6.3) 5 (14.3) 13 (34.9) 17 (61.9) 7 (73.0) 14 (95.2) 1 (96.8) 1 (98.4) 1 (100.0) Meropenem 1 (1.6) 0 (1.6) 1 (3.2) 3 (7.9) 29 (54.0) 18 (82.5) 6 (92.1) 2 (95.2) 3 (100.0) Castanheira M et al. Antimicrob Agents Chemother. 2017 Aug 24;61(9)
Mero Vabor Vs Pip/Tazo? Phase 3, MC, MN, RCT (TANGO I) conducted 11/ 2014 to 4/ 2016 Patients ( 18 years) with c UTI, stratified by infection type and geographic region 27
TANGO I For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-tazobactam (difference, 4.5% [95% CI, 0.7% to 9.1%]; P <.001 for noninferiority). How do you translate these studies to CREs? MDROs?
TANGO-2: Meropenem-vaborbactam vs. Best Available Therapy Serious Infection: Bacteremia, pneumonia, cuti, ciai 72 patients 43 with CRE, 20 with bacteremia; 86% K. pneumoniae DSMB: risk-benefit analysis no longer supported randomization of additional patients to the best available therapy comparator arm Kaye K et al. IDWeek 2017. Abst 1826
Ceftolozane-tazobactam Structure Class and spectrum New cephalosporin + tazobactam- class A β- lactamase inhibitor Potent against P. aeruginosa: High affinity for penicillin binding proteins (PBP) Stable against class C β-lactamases (AmpC) Does not use OprD porin Not a substrate of effux pumps Active against (some) ESBLs Does not inhibit KPC, OXA or metallo-βlactamases
In the real world : Ceftolozane/tazobactam to treat carbapenem-resistant P. aeruginosa 35 patients, 18 pneumonia, 3 cystic fibrosis, 6 bacteremia In vitro susceptibility to C/T (n=30): S =26 (87%), I = 2, R = 2 (MIC 16-48 μg/ml) Pan-resistant to β-lactams = 23; C/T S = 19 (83%) Monotherapy in 27 (77%); cipro or colistin IV; tobra o colistin inh. 26 cures (74%), 6 failures, 3 dead Therapeutic failure in every case with C/T CIM 8 μg/ml Diarrhea without C. difficile (n=1) Eosinophilia without nephritis (n=1) Munita JM. Clin Infect Dis 2017 en prensa
Unmet needs Carbapenem-resistant Acinetobacter, typically producing OXA-23, OXA-24/40, and OXA-58 carbapenemases Metallo-beta-lactamase producing organisms
New Approaches Acinetobacter
Imipenem + Relebactam
Meropenem + Nacubactam
Structure and mechanism Cefiderocol Class and Spectrum Novel siderophore cephalosporin Promising in vitro activity (MIC < 4 mcg/ml): Enterobacteriaceae - 87.5% P. aeruginosa - 100% A. baumanii - 89% Stable against carbapenemases, including some metallo-betalactamases Class A 91.8% Class B 74.8% Class D 98.0% IDWeek 2017. Abstract 1230
Cefiderocol vs imipenem in acute complicated urinary tract infection and pyelonephritis - APEKS-cUTI Response at Test of Cure in Microbiological Intent-to-Treat Population *Primary endpoint superiority to imipenem! Awaiting regulatory approval Portsmouth et al. IDWeek 2017. Abstract 1869
Sulbactam Activity as a β-lactamase inhibitor Also a β-lactam with intrinsic activity against A. baumannii Extensively use to treat A. baumannii β-lactamase-mediated resistance now common with MIC 90 >32 mg/l ETX2514 Novel β-lactamase inhibitor Potent broadspectrum inhibitor of Class D β-lactamases Also potent broadspectrum inhibitor of Class A and C β- lactamases
New Approaches MDR MBL GNRs
At 2 h 4 log 10 decrease in CFU in time-kill assays (ATM 8 mg/l) 4 log 10 decrease in thigh infection (32 mg/kg CZA and 32 mg/kg ATM) NDM producers
ATM placed directly on the CAZ-AVI disk to evaluate synergy in E. cloacae producing NDM-1, CTX-M-15, ACT/MIR and OXA-48 21 isolates resistant to CAZ and CAZ-AVI 16 became susceptible with addition of ATM Adding a higher concentration of ATM made the 5 remaining susceptible Marshall SM et al. Antimicrob Agents Chemother 2017
Stenotrophomonas L1 and L2 Disk diffusion susceptibility testing of the MDR S. maltophilia isolate in MH agar. CAZ: ceftazidime; AZT: aztreonam; CZA: ceftazidimeavibactam; IMI: imipenem. Note the synergy between CZA and AZT. Ceftazidime-avibactam (CZA) and aztreonam (AZT) Mojica et al AAC 2016
HN N O O H N O Zidebactam N N WCK 4234 N H O N - OSO Na + 3 N OSO 3 H NaO HN New Drugs: BLIs and BLEs O O N N H N O O O N HN (A, DBO sodium salt) Relebactam N OSO 3 H O H N N H O N O WCK 5153 H 2 N O O N N Avibactam N OSO 3 H - OSO Na + 3 The key medicinal chemistry challenge involved identifying a side chain (R1) at the C-2 position of the DBO core that was able to penetrate the periplasmic space of Gram negative bacteria and access PBP targets on the cytoplasmic membrane Figure 1. Chemical Structures of DBOs used in this study
Novel DBOs: forging new paths WCK 4234 WCK 5107 WCK 5153 1. BLEs represent a new antimicrobial class and work by providing complimentary PBP inhibition to a partner β-lactam. 2. By targeting two different PBPs, BLEs act synergistically (P. Aeruginosa and A. baumannii) 3. Operate independently of BLIs. Moya, Papp-Wallace,.. Bonomo AAC 2017
A murine neutropenic lung infection model using A. baumannii SL06 carrying blaoxa-23 and blaoxa-51. The graphs represent the change in CFU/lung after different antibiotic treatments administered as q2h. A. Cefepime at 50 mg/kg (FEP), meropenem:cilastatin at a 1:1 ratio of 25 mg/kg (MEM:CLS), and imipenem:cilastatin at a 1:1 ratio of 25 mg/kg (IPM:CLS). B. Cefepime zidebactam at 50 mg/kg and 8.33 mg/kg, respectively (FEP-ZID), meropenem:cilastatin at a 1:1 ratio of 25 mg/kg and 4.68 mg/kg of WCK 4234 (MEM:CLS-WCK 4234), and imipenem:cilastatin at a 1:1 ratio of 25 mg/kg and 18.75 mg/kg of relebactam (IPM:CLS- REL).
1. Putting it all together 47
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Develop a new approach Identify patients at risk and understand the genetic complexity of CRE as a guide to informed treatment decisions General Principles First dose supremacy Real Time testing Define the molecular basis Develop a Predictive Model New Drugs ImmunoRx?
Determine the Molecular Basis of Resistance
Find new drugs or combination therapies
In 7 (18%) cases, the number of antibiotics used in combination empirically was reduced by the iact service. Overall, low 30-day infection-related mortality (15%) and high clinical response (82%) were observed. Microbiological eradication was observed in 79% of all bloodstream infections.
Profiled almost 3,000 dose-resolved atb combos, humantargeted drugs and food additives in 6 strains from three Gram-negative pathogens Escherichia coli, Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa to identify general principles for antibacterial drug combinations and understand their potential. > 70% of the drug drug are species-specific and 20% display strain specificity, revealing a large potential for narrow-spectrum therapies.
It gets complex.. You need a plan Overall, antagonisms are more common than synergies and occur almost exclusively between drugs that target different cellular processes, whereas synergies are more conserved and are enriched in drugs that target the same process.
So. Are we finally ready for ImmunoRx?
EVs are spherical nm-sized proteolipids enriched with outer membrane proteins. EV vaccination via the intraperitoneal route elicited EVreactive antibodies and IFN-γ, IL-17 and IL-4 in CD4+ cells Adoptive transfer of sera and splenocytes confer protection against K. pneumonia-induced lethality
K1-CPS-specific IgG Abs were generated by conjugation of K1-CPS to immunogenic anthrax protective antigen (PA) protein. mabs worked in PNA and sepsis
In summary, these 2 MAbs can be considered candidates for an antibody-based approach to the treatment of CR K. pneumoniae-infected patients otherwise with limited therapeutic options. Furthermore, glycan array binding studies highlight the importance of previously described hexasaccharide 1, which constitutes a relevant epitope on all of the clade 2 strains tested. This oligosaccharide should be further explored for vaccine development.
CAUTION!!
Summary Extraordinary threat to public health We have learned a tremendous amount Combos seem to be effective vs. KPC but not Acineto? but we still need to design the right trial to answer the fundamental question as to why Knowing the genetic context is necessary to inform therapy Need to carefully look at the new drugs in the pipeline as they are released Consider new approaches?? Think outside the box! Develop the clinical and scientific models as a basis for informed therapy No time to loose.need to connect lab to the clinic CRACKLE,PRIMERS, ARLG Bedside and bench: Past antibiotic history, look at what is left over, need to worry about what we don t know
Current Conclusions Its very complicated..we have to live with imperfection. Better the antibiotic, the better the outcome?? One good drug is better than two bad ones?? Despite limitations, observational studies support combination therapy when done correctly in high risk and very ill patients (right drugs, rapid molecular diagnostic, TDM, defined genotype etc.) may be beneficial or superior to monotherapy. This will not be true in all cases. What should we do about this?
Bacteria No time to lose : Forward looking clinical trials based upon sound theory should be our mandate need to marry hypothesis testing at the bench to the clinic