Confronting MDR_IDWeek 2023_combined slideset_downloadable.pptx

Confronting MDR_IDWeek 2023_combined slideset_downloadable.pptx

1. The X Factor: Following the Science to Confront MDR, DTR, and XDR Gram-Negative Infections

2. Burden of Antimicrobial Resistance

3. 2019: Global Impact of Antimicrobial Resistance Estimated 4.95 million deaths associated with bacterial AMR, including 1.27 million deaths attributed to bacterial AMR Antimicrobial Resistance Collaborators. Lancet. 2022;399:629. Deaths (Count) 900,000 600,000 300,000 Escherichia coli Staphylococcus aureus Klebsiella pneumoniae Streptococcus pneumoniae Acinetobacter baumannii Pseudomonas aeruginosa Mycobacterium tuberculosis Enterococcus faecium Enterobacter spp Group B Streptococcus Salmonella enterica serotype Typhi Enterococcus faecalis Proteus spp Other enterococci Serratia spp Group A Streptococcus Citrobacter spp Haemophilus influenzae Shigella spp Nontyphoidal Salmonella Salmonella enterica serotype Paratyphi Morganella spp Pathogen Resistance Associated with resistance Attributable to resistance

4. In a retrospective analysis of 10,628 BSI episodes (N = 9192), ≥12-hr delay in TTET associated with increased mortality 1 Delays in TTET also associated with longer hospital/ICU length of stay and longer time to fever and symptom resolution 2-5 Landmark Time Inappropriate Therapy Events (Episodes) Appropriate Therapy Events (Episodes) Risk of Mortality Adjusted Odds Ratio (95% CI) Total cohort 1 hr 750 (7022) 447 (3266) 0.83 (0.72-0.95) 3 hr 530 (4699) 631 (5346) 1.00 (0.87-1.15) 6 hr 392 (3404) 730 (6458) 1.05 (0.91-1.22) 12 hr 323 (2594) 752 (7129) 1.17 (1.01-1.37) 24 hr 227 (1755) 776 (7837) 1.24 (1.04-1.47) 48 hr 150 (1092) 784 (8461) 1.41 (1.15-1.74) 72 hr 99 (657) 768 (8908) 1.67 (1.30-2.15) Impact of Delayed Time to Effective Therapy 1. Van Heuverswyn. Clin Infect Dis. 2023;76:469. 2. Piskin. BMC Infect Dis. 2012;12:268. 3. Clec’h. Intensive Care Med. 2004;30:1327. 4. Kalil. Clin Infect Dis. 2016;63:e61. 5. Falcone. Crit Care. 2020;24:29.

5. 3 Global Rates of CRE Kazmierczak. Antimicrob Agents Chemother. 2021;65:e0200020. 2012-2014 2015-2017 2012-2014 2015-2017 2012-2014 2015-2017 2012-2014 2015-2017 2012-2014 2015-2017 2012-2014 2015-2016 Global Latin America Europe Asia/South Pacific Middle East/Africa North America 6 5 4 2 1 Collected Isolates (%) VIM NDM IMP OXA-48 – like GES KPC No carbapenemase detected

6. Global Carbapenem-Resistant P. aeruginosa CRPA isolated from 927 patients from 10 countries Resistance etiology varied by region Increased 30-day mortality with carbapenemase- vs non – carbapenemase-producing CRPA (22% vs 12%; difference: 9%; 95% CI: 3%-16%) Reyes. Lancel Microbe. 2023;4:e159. ≥2 carbapenemase genes bla GES bla IMP bla KPC bla NDM None Other carbapenemase gene bla VIM US (n = 527) 6 (1%) 3 (1%) 517 (98%) South and Central America (n = 127) 23 (18%) 23 (18%) 41 (32%) 39 (31%) 1 (1%) Australia and Singapore (n = 56) 3 (5%) 12 (21%) 12 (21%) 24 (43%) 4 (7%) 1 (2%) China (n = 171) 2 (1%) 3 (2%) 40 (23%) 117 (68%) 1 (1%) 1 (1%) 7 (4%) Middle East (n = 91) 16 (18%) 7 (8%) 4 (4%) 64 (70%)

7. US Outbreak of XDR P. aeruginosa Outbreak reported by CDC in early 2023 of XDR P. aeruginosa in 81 patients in 18 states (4 deaths) linked with contaminated artificial tears (numerous brands) and VIM-GES-carbapenemase ‒ producing P. aeruginosa WARNING

8. 2023 IDSA Gram-Negative Resistance Categories idsociety.org/practice-guideline/amr-guidance

9. Spectrum of Activity Overview 1 Agent Enterobacterales MBL producer CR- P. aeruginosa 2,3 CR- A. baumannii 4 KPC MBL Ceftolozane/tazobactam Ceftazidime/avibactam Meropenem/vaborbactam Imipenem/relebactam Sulbactam/durlobactam Aztreonam/avibactam Cefiderocol Eravacycline Polymyxin B or colistin Susceptibility anticipated to be >80% Susceptibility may vary by location; may range from 30%-80% or be >80% Intrinsic resistance or susceptibility anticipated to be <30% 1. Tamma. J Pediatric Infect Dis Soc. 2019;8:251. 2. Pfaller. Int J Infect Dis. 2021;112:321. 3. Sader. Antimicrob Agent Chemother. 2017;61:e01045 . 4. Karlowsky. Antimicrob Agents Chrmother. 2022;66:e00781. Susceptibility anticipated to be 30%-80% Data no t available

10. Carbapenem-Resistant A. baumannii

11. Mechanisms of β-lactam Resistance: CRAB Reduced outer membrane permeability Upregulated efflux pumps Inactivation of drug by enzymes Mutations of drug target Antibiotic Gram-Negative Bacterium Changes in porin expression Resistance mechanisms can co-occur idsociety.org/practice-guideline/amr-guidance. Corvec. J Antimicrob Chemother. 2003;52:629. Castanheira. JAC Antimicrob Resist. 2021;3:dlab092. Carbapenemases: OXA-23, OXA-24/40 ‒ like, and OXA-58 ‒ like; MBL (rare) Other β- lactamases: ESBL, AmpC Alterations in PBPs (eg, PBP1a/1b and PBP3 for SUL)

12. Resistance Mechanisms and Virulence Factors: Additional Considerations for CRAB Often resistant to other antibiotics, as well as carbapenems, such as 1,2 : Fluoroquinolones due to topoisomerase modifications Aminoglycosides due to 16S rRNA methyltransferase Biofilm formation associated with resistant phenotypes and enhanced virulence 3 Mechanisms of underlying resistance are geographically specific 4 1. idsociety.org/practice-guideline/amr-guidance. 2. Ruppe. Ann Intensive Care. 2015;5:61. 3. Bardbari. Microb Pathog 2017;108:122. 4. Seifert. J Glob Antimicrob Resist. 2022;31:82.

13. 2023 IDSA Guidance: Moderate to Severe CRAB Infections Combination therapy with ≥ 2 active agents whenever possible (even if a single agent demonstrates activity) until clinical improvement idsociety.org/practice-guideline/amr-guidance

14. Role of Sulbactam Against CRAB SUL, at high doses, competitively and irreversibly binds to PBP1a, PRP1b and PBP3 against A. baumannii 1,2 Not interchangeable with other β -lactamase inhibitors Retains activity against some strains that produce OXA-23 carbapenemase 3 Ampicillin/SUL MICs = surrogate for SUL activity if susceptible (≤8/4 mg/L), but not when resistant 3,6 Ampicillin/SUL 3 g Q6H over 1 hr: >90% probability of achieving 40% fT > MIC for isolates with MICs ≤16 mg/L SUL 6-12 g per day can result in adequate exposure for MICs 16-32 mg/L Safety data for higher SUL doses limited Infection Severity Ampicillin/Sulbactam* Dosing Recommendations Mild 3 g (1 g SUL/dose) Q4H over 30 min 4 Moderate to severe 9 g (3 g SUL/dose) Q8H over 4 hr 5 27 g (9 g SUL) Q24H as CI 6 1. Wang. Infect Drug Resist. 2021;14:3971. 2. idsociety.org/practice-guideline/amr-guidance. 3 . Abdul-Matakabbir. Infect Dis Ther. 2021;10:2177. 4 . Lenhard. Antimicrob Agents Chemother. 2017;61:e01268-16. 5. Betrosian. Scan J Infect Dis. 2007;39:38. 6. Jaruatanasirikul. Eur J Pharm Sci. 2019;136:104940 . *3 g = ampicillin 2 g/sulbactam 1 g.

15. Meropenem + Colistin for CRAB Study Study Design Results AIDA 1 Randomized, international, multicenter, open-label trial comparing meropenem/colistin (n = 208) vs colistin monotherapy (n = 198) in patients with BSI, HAP/VAP, or urosepsis caused by carbapenem nonsusceptible gram-negative bacteria Majority with pneumonia or BSI (87%); most infections caused by CRAB (77%) No difference in clinical failure at 14 days in patients with CRAB (RR: 0.97; 95% CI: 0.87-1.09) OVERCOME 2 Randomized, international, multicenter, double-blind, placebo-controlled study comparing colistin + meropenem (n = 210) vs colistin + placebo (n = 213) for XDR gram-negative or CRE infections ~70% pneumonia, ~30% BSIs; most common organism was A. baumannii (78%) No difference in 28-day mortality in patients with CRAB between meropenem + colistin vs colistin + placebo (37% vs 43%; P = .17 ) 1. Paul. Lancet Infect Dis. 2018;18:391. 2. Kaye. NEJM Evid. 2022;2:EVIDoa2200131. 3 . idsociety.org/practice-guideline/amr-guidance. Is it time to sunset this combination? Meropenem + colistin (without addition of third agent) is not suggested option for CRAB treatment by IDSA guidance 3

16. The Triple Threat: 3-Drug Regimen With Carbapenem + Sulbactam + Polymyxin B Against CRAB Mechanism: Polymyxins facilitate increased access for ampicillin/sulbactam and carbapenems; enable complete saturation of PBP1/3 and PBP2 1 Time-kill studies indicate increased killing with this 3-drug combo vs 2-drug combos Because high-dose ampicillin/sulbactam is suggested as core component of combination treatment, IDSA guidance advises against use of high-dose, extended-infusion carbapenems , as they may lead to additive β -lactam toxicity without clinical benefit 4 1. Lenhard. Antimicrobial Agents Chemother. 2017;72:1415. 2. Qureshi. Clin Infect Dis. 2015;60:1295. 3. Heil. J Antimicrob Chemother. 2023;78:1034. 4. idsociety.org/practice-guideline/amr-guidance. May reduce emergence of resistance 3 In single center that underwent outbreak of CRAB infections in 18 patients with COVID-19, no emergence of resistance observed with early initiation of dose-optimized 3-drug regimen Potential mortality benefit 2 In observational study of patients with colistin-resistant CRAB infections, 30-day mortality was 0% (0/7) with 3-drug regimen vs 60% (6/10) with other regimens ( P = .03)

17. Tetracyclines Against CRAB Data for use almost exclusively in combination with other agents Unlikely f AUC:MIC targets can be reached with standard dosing regimens PK/PD limitations in serum, urine, and ELF Limited clinical data for eravacycline ; no clinical data for omadacycline As part of combination regimen When MICs are low (eg, ≤1 mg/L for tigecycline and minocycline) Infection sites where PK/PD can be optimized (eg, skin/soft tissue or osteoarticular) At optimized dosing: Minocycline 200 mg Q12H Tigecycline 100 mg Q12H Limitations May be useful... Shields. Clin Infect Dis. 2023;76(suppl 2):S179. Flamm. Antimicrob Agents Chemother. 2019;63:e01154. Xie. Antimicrob Agents Chemother. 2017;61:e00345.

18. Cefiderocol Against CRAB CREDIBLE-CR: randomized phase III trial comparing cefiderocol vs BAT in patients with nosocomial pneumonia, BSI, sepsis, or cUTI due to carbapenem-resistant gram negatives 1 APEKS-NP: randomized phase III study comparing cefiderocol vs high-dose extended infusion meropenem for nosocomial pneumonia 2 No difference in all-cause mortality at Day 14 in patients with Acinetobacter s pp and meropenem MIC >8 mg/mL (n = 53) All-Cause Mortality at End of Study , n/N (%) Cefiderocol (n = 101) BAT (n = 49) Overall 34/101 (34) 9/49 (18) Acinetobacter spp 21/42 (50) 3/17 (18) Acinetobacter baumannii 19/39 (49) 3/17 (18) Klebsiella pneumoniae Without Acinetobacter spp 8/34 (24) 6/28 (21) 4/16 (25) 4/15 (27) Pseudomonas aeruginosa Without Acinetobacter spp 6/17 (35) 2/11 (18) 2/12 (17) 2/11 (18) In observational, retrospective study, use of cefiderocol vs colistin-containing regimens for CRAB infections was associated with 3 : Significantly lower 30-day all cause mortality ( 34% vs 55.8%, P = .018) Benefit driven by BSI, not observed with VAP Higher rates of microbiological failure (17.4% vs 6.8%; P = .079) 1. Bassetti. Lancet Infect Dis. 2021;21:226. 2 . Wunderink. Lancet Infect Dis. 2021;21:213. 3. F alcone. Antimicrob Agent Chemother. 2022;66:e0214221.

19. Regimens with high-dose extended-infusion carbapenem therapy, such as: Meropenem + colistin or polymyxin B Meropenem + ampicillin/sulbactam + minocycline or polymyxin B Fosfomycin or rifampin as components of combination therapy Nebulized antibiotic as adjunctive therapy 2023 IDSA Guidance Summary: Moderate to Severe CRAB Infections High-dose ampicillin/sulbactam (even if nonsusceptibility is demonstrated ) in combination with at least 1 additional active agent, such as: Polymyxin B M inocycline or tigecycline (high dose) C efiderocol Limit to infections refractory to other options, or if intolerance/resistance to other agents Suggested Regimens Regimens to Avoid idsociety.org/practice-guideline/amr-guidance

20. Overview of Sulbactam/Durlobactam FDA approved in May 2023 for HABP/VABP treatment SUL/DUR 1 g/1 g Q6H over 3 hr DUR: β -lactamase inhibitor; inhibits OXA carbapenemases Lowers sulbactam MICs by 32-fold against CRAB Dosage validated in population PK studies of infected and healthy subjects Target attainment of AUC:MIC of 10 achieved for >90% of isolates with SUL/DUR MIC ≤4 mg/L PK data in healthy individuals suggest high probability of target attainment in ELF concentrations Durand-Reville. Nat Microbiol. 2017;2:17104. Papp-Wallace. Clin Infect Dis. 2023;76:S194. Bhavnani. IDWeek 2022. Abstr LB2306. Shields. Clin Infect Dis. 2023;76:S179.

21. ATTACK: Sulbactam/Durlobactam vs Colistin for A. baumannii complex HABP/VABP or BSI 2-part study: ( part A ) multicenter, randomized, blinded, noninferiority phase III trial; ( part B ) open-label study of patients with colistin-resistant (MIC ≥4 µg/mL) CRAB infections Kaye. Lancet Infect Dis. 2023;23:1072. Part A Hospitalized adults aged ≥18 yr with ABC-confirmed HABP/VABP, ventilated pneumonia, or BSI (N = 125) SUL/DUR 1 g/1 g IV Q6H + IMI (n = 63) Colistin 2.5 mg/kg Q6H + IMI (n = 62) Primary outcome: 28-day all-cause mortality in CRAB m-ITT population (20% noninferiority margin) Key secondary outcomes: 14-day all-cause mortality (CRAB m-ITT population), clinical cure at ToC, rates of nephrotoxicity (measured by RIFLE) 7-14 days Part B Patients not eligible for Part A (colistin resistant or intolerant) SUL/DUR 1 g/1 g IV Q6H + IMI (n = 28) Imipenem/cilastatin dose: 1 g/1 g q6H. 7-14 days

22. ATTACK: Clinical and Safety Outcomes Part A -13.2% (-30% to 3.5%) P < .001 -13% (-25.7% to 0.1%) 22% (2.9% to 40.3%) Patients (%) Kaye. Lancet Infect Dis. 2023;23:1072. Miller. Open Forum Infect Dis. 2022;ofac492.303. 12/63 20/62 39/63 25/62 12/91 32/85 4/64 12/63 Part B 28-day all-cause mortality: 18% (most patients with BSI) Clinical cure at ToC: 71% Part A Compared with participants in colistin arm, those in SUL/DUR arm had: Higher rates of microbiologic response at EoT (86% vs 61%) and ToC (68% vs 42%) Higher rates of recurrence (10% vs 3%)

23. SUL/DUR + Carbapenems Carbapenem + sulbactam: synergistic combination based on complementary PBP binding activity 1,2 Based on in vitro data, imipenem lowers MIC 50 of SUL/DUR 2- to 4-fold 3 In hollow fiber infection model, addition of a carbapenem (imipenem, meropenem) to SUL/DUR was evaluated against CRAB isolates 4 For isolates with MIC 4 mg/L (preliminary breakpoint), no effect on efficacy observed (eg, %T > MIC), but improved activity seen for isolates outside this susceptibility range Imipenem and meropenem displayed similar activity Difficult to attribute ATTACK study results solely to SUL/DUR activity 1. Choi. Clin Microbiol Infect. 2004;10:1098. 2. Ko. Antimicrob Chemother. 2004;53:393. 3. Iovleva. ECCMID 2023. Abstr 154. 4. Tanudra. ECCMID 2022. Abstr 2037.

24. Take-home Points: CRAB Individualized treatment regimens are needed based on infection site, susceptibility testing results, and local epidemiology for CRAB Treatment regimens should include sulbactam backbone Sulbactam /durlobactam (± carbapenem), or Ampicillin/ sulbactam + at least 1 more in vitro active antibiotic (eg, polymyxin B, tetracycline derivative, cefiderocol) In vitro activity should not rely on susceptibility breakpoints alone Need to understand antimicrobial PK/PD targets and drug exposures at site of infection Shields. Clin Infect Dis 2023;76(suppl 2):S179.

25. Carbapenem-Resistant Enterobacterales

26. Ambler Classification of β -lactamases Ambler Class Examples Organisms Drugs Impacted A: Penicillinases KPC* TEM SHV CTX-M Enterobacterales Pseudomonas spp. Extended-spectrum cephalosporins, carbapenems, aztreonam Variable susceptibility to clavulanic acid (most susceptible except KPC) B : metallo- β- lactamase IMP* VIM* NDM* Acinetobacter baumannii K. pneumoniae P. aeruginosa Stenotrophomonas maltophilia Resistant to all β -lactams except monobactams (aztreonam); resistant to clavulanic acid, tazobactam, sulbactam May harbor additional resistance genes C: Cephalosporinases CMY* AmpC Enterobacterales ( Enterobacter, Citrobacter, Serratia, Proteus ) Pseudomonas spp. Penicillins, cephalosporins/cephamycins, β -lactam/ β -lactamase inhibitors Cefepime and aztreonam may retain activity D: Oxacillinases OXA* (OXA-23, 24, 48, 146) A. baumannii P. aeruginosa E. coli Extended-spectrum cephalosporins and carbapenems Hall. J Antimicrob Chemother. 2005;55:1050. *Carbapenemase.

27. Carbapenem-Resistant Enterobacterales Resistance Carbapenemase producing Non-carbapenemase producing Class A eg, KPC Class B (metallo- b -lactamases) eg, NDM, VIM Class D eg, OXA-48 High-level resistance Low-level resistance b -lactamases ↑ Efflux ↓ Permeability Multifactorial Carbapenem-resistant gram-negative bacteria cdc.gov/hai/organisms/cre/technical-info.html. Tamma. Clin Infect Dis. 2021;72:109. Nordmann. Clin Infect Dis. 2019;69:S521.

28. 2023 IDSA Guidance: CRE Outside Urinary Tract Preferred Alternative Options (First Line Not Available) Carbapenem-resistant Enterobacterales KPC identified, or carbapanemase testing results not available or negative Meropenem/vaborbactam Ceftazidime/avibactam Imipenem/cilastatin/relebactam Cefiderocol Tigecycline or eravacycline Not recommended for treatment of UTIs or BSIs NDM, VIM, IMP identified Ceftazidime/avibactam + aztreonam Cefiderocol Tigecycline or eravacycline Omadacycline is not recommended Generally reserved for IA infections Not recommended for treatment of UTIs or BSIs OXA-48-like carbapenemase identified Ceftazidime/avibactam Cefiderocol idsociety.org/practice-guideline/amr-guidance

29. Dosing Considerations Dose: CAZ/AVI 2.5g Q8H + aztreonam 2g Q6H Infuse both over 3 hr Give simultaneously instead of sequentially or continuously Paneled orders in EMR recommended to facilitate appropriate dosing Ceftazidime/Avibactam + Aztreonam Against MBL-Producing Enterobacterales In prospective study evaluating MBL-producing Enterobacterales BSIs (NDM: 82 patients; VIM: 20 patients), c ompared with other active antibiotics arm (n = 50), those in CAZ/AVI + ATM arm ( n = 52) had: L ower 30-day mortality: 1 9.2% vs 44%, P = .007 L ower clinical failure rates at Day 14: HR: 0.30 (95% CI: 0.14 -0 .65) S horter length of stay from BSI onset: s HR: 0.49 (95% CI : 0.30-0.82 ) Falcone. Clin Infect Dis. 2021;72:1871. Lodise. J Antimicrob Chemother. 2020;75:2622. idsociety.org/practice-guideline/amr-guidance. Falcone. 2021;72:1871.

30. Aztreonam/Avibactam: Phase III Studies REVISIT: randomized, multicenter phase III study evaluating ATM/AVI ± MTZ vs MEM ± COL Subset of patients with MBL-positive cultures (n = 10): clinical cure achieved in 2 of 7 patients (28.6%) in ATM/AVI ± MTZ arm vs 2 of 3 patients (66.7%) in MER ± COL arm Majority had previous treatment failure at enrollment ASSEMBLE: randomized, multicenter phase III study evaluating ATM/AVI vs BAT for treatment of MBL-producing gram-negative infections Cure rates at ToC: 41.7% (5/12) in ATM/AVI arm vs 0% (0/3) in BAT arm Endpoint, n/N (%) ATM/AVI ± MTZ MEM ± COL Treatment Difference %, (95% CI) Clinical cure at ToC cIAI HAP/VAP 159/208 (76.4) 34/74 (45.9) 77/104 (74) 15/36 (41.7) 2.4 (-12.4 to 19.1) 4.3 (-25.6 to 32.2) 28-day all-cause mortality cIAI HAP/VAP 4/208 (1.9) 8/74 (10.8) 3/104 (2.9) 7/36 (19.4) -- Carmeli . IDWeek 2023. Abstr 262. NCT03329092. NCT03580044. pfizer.com/news/press-release/press-release-detail/phase-3-studies-pfizers-novel-antibiotic-combination-offer. Disclaimer: Data are from press release only and have not been presented at a scientific congress or peer reviewed.

31. CREDIBLE-CR and APEKS-NP: Cefiderocol Against MBLs Randomized, multicenter phase III controlled trials Pooled data of infections caused by MBL producers Monotherapy cefiderocol (n = 24) found to be effective compared with BAT or high-dose meropenem (n = 10) Clinical cure at ToC was lower for NDM (9/16, 56.3%) than for non-NDM (8/8, 100%) infections Timsit. Clin Infect Dis. 2022;75:1081. Patients (%)

32. NDM-Producing E. coli With Pan- β -Lactam Resistance Whole genome sequence performed; proposed mechanisms of resistance include: Modified PBP3 Truncated iron-binding protein bla CMY gene Antimicrobial susceptibility testing performed on investigational BL-BLI First clinical case of US patient with NDM-producing E. coli and resistance to cefiderocol and ceftazidime/avibactam Patient traveled to India for renal transplant from living related donor Agent MIC, µg/mL Cefepime/taniborbactam 16/4 Cefepime/zidebactam ≤0.25/0.25 Meropenem/xeruborbactam ≤0.25/8 Simner. Open Forum Infect Dis. 2023;10:ofad276.

33. Take-home Points: CRE Several mechanisms of resistance can result in CRE Non ‒ carbapenemase-producing CRE is often multifactorial (eg, β -lactamase + upregulated efflux pumps) CRE treatment driven by carbapenemase present If carbapenemase testing results unavailable or negative, treat for KPC unless patient with risk factors for other carbapenemases For MBL-producing Enterobacterales , preferred treatment options include: (1) ceftazidime/avibactam + aztreonam or (2) cefiderocol Ceftazidime/avibactam + aztreonam should be administered simultaneously

34. P. aeruginosa With Difficult-to-Treat Resistance

35. Mechanisms of β-lactam Resistance: DTR- P. aeruginosa Reduced outer membrane permeability Upregulated efflux pumps Inactivation of drug by enzymes Mutations of drug target Antibiotic Gram-Negative Bacterium 4 OprD downregulation 1,3 : major contributor to carbapenem resistance (eg, imipenem, reduced susceptibility to meropenem) Any can co-occur with other resistance mechanisms; multiple mechanisms are present in DTR strains 1. Livermore. Clin Infect Dis. 2002;34:634. 2. Torrens. mSystems. 2019;5:e00524. 3. Xu. Infect Drug Resist. 2020;13:1419. 4. Peleg. N Engl J Med. 2010;362:1804. MexAB-OprM upregulation 1 : reduced susceptibility to meropenem (not imipenem) β-lactamase 1,2 : AmpC (most common), ESBL, MBL (eg, VIM, IMP, NDM)

36. Effect of Resistance Mechanism on Susceptibility to Antipseudomonal Drug Resistance to one β -lactam does not necessarily mean resistance to others Antibiotic Porin Reduction AmpC β -Lactamase/Pseudomonal-Derived Cephalosporinase Efflux Pumps Ceftazidime -- Resistance (usually) Reduced susceptibility or resistance Cefepime -- Can have resistant MICs in presence of high amounts of enzyme Reduced susceptibility or resistance Piperacillin/ tazobactam -- Resistance (usually) Reduced susceptibility or resistance Meropenem Reduced susceptibility (alone, unlikely to be R) -- Reduced susceptibility (alone, unlikely to be R) Imipenem Resistance usually seen Elevated MICs, but susceptibility retained -- Livermore. Clin Infect Dis. 2002;34:634.

37. 2023 IDSA Guidance: DTR- P. aeruginosa Recommendation 1 Regimen for Outside Urinary Tract Expanded Activity Against DTR- P. aeruginosa 2 Preferred Ceftolozane/tazobactam Less affinity for hydrolysis by AmpC β -lactamase and PDCs Not affected by OprD loss Weak substrate for efflux systems Ceftazidime/avibactam Inhibits several β -lactamases, including OXA-48 Imipenem/cilastatin/ relebactam Not substrate for efflux pumps Activity preserved in AmpC β -lactamase hyperproduction Alternative Cefiderocol (preferred for MBL-producing isolates) Stable to both serine and metallo- β -lactamases Active transport across outer membrane of gram-negatives Not Recommended Addition of nebulized antibiotics Combination therapy when susceptibility to preferred β-lactams demonstrated If no preferred β-lactams demonstrate activity, tobramycin (or polymyxin B if resistant) can be considered with one of the preferred/alternative β-lactams 1. idsociety.org/practice-guideline/amr-guidance. 2. O’Donnell. Pharmacotherapy. 2020;40;952. Meropenem/vaborbactam provides no added activity vs meropenem alone

38. Activity Against Newer Antipseudomonal β -lactams From 2020-2021 in US In vitro activity of 3184 isolates against newer β -lactams were assessed from 71 centers Sader. Int J Antimicrob Agents. 2023;61:106744. Resistance Phenotype (n) Susceptibility, % Criteria CAZ/AVI C/T IMI/REL CAZ/AVI, C/T, or IMI/REL CAZ/AVI nonsusceptibility (95) -- 54.7 64.2 82.1 C/T nonsusceptibility (63) 31.7 -- 64.8 73 IMI/REL nonsusceptibility (61) 52.5 68.9 -- 72.1

39. Ceftolozane/Tazobactam for DTR- P. aeruginosa Study Study Design Results Holger 1 Retrospective, multicenter study comparing (C/T) (n = 118) vs BAT (n = 88) for MDR/XDR P. aeruginosa LRTI C/T arm: XDR phenotype, VAP, and use of combo more common Lower rates of clinical failure in C/T vs BAT (23.7% vs 48.9%; P <.001) In multivariate regression, C/T protective against clinical failure (adjusted OR: 0.27; 95% CI: 0.14-0.51) No difference in 30-day mortality (C/T 15.3% vs BAT 20.5%; P = .331) Caffrey 2 VA-wide retrospective study comparing C/T (n = 57) vs aminoglycoside- or polymyxin-based therapies (n = 155) for MDR P. aeruginosa infections C/T arm: younger, more likely from LTCF, higher comorbidity burden ; higher portion of bone/joint infections and fewer UTIs Lower inpatient mortality with C/T vs comparator arm (15.8% vs 27.7%; adjusted OR: 0.39; 95% CI: 0.16-0.93) No differences in other outcomes (eg, 30-day hospital readmission, persistent positive culture, microbiological clearance, and AKI) Chi 3 Meta-analysis (N = 13; 6 RCTs, 4 cohort, 3 case control) of C/T vs primarily aminoglycoside or colistin-based regimens for GNR infections 6 studies on P. aeruginosa infections (C/T 305 patients vs comparator 636 patients), of which 5 studies evaluated MDR/XDR isolates Higher clinical cure rates with C/T (OR: 2.62; 95% CI 1.31-5.26) 1. Holger. Infect Dis Ther. 2022;11:1965. 2. Caffrey. Antibiotics (Basel). 2022;11:626. 3. Chi. Expert Rev Anti Infect Ther. 2023;21:189.

40. Ceftazidime/Avibactam for MDR P. aeruginosa Pneumonia Pooled analysis of 5 randomized phase III trials of CAZ/AVI vs comparator for MDR P. aeruginosa infections (n = 95) 5 studies on cUTI and/or cIAI; 1 study on nosocomial pneumonia Carbapenem used in all trials except 1 that used carbapenem-based BAT Similar clinical cure rates at ToC with CAZ/AVI (57.1%) vs comparator (53.8%) Retrospective, multicenter cohort study of ceftazidime/avibactam timing of administration in MDR P. aeruginosa pneumonia (N = 115) CAZ/AVI administration within 48 hr ( early ) vs >48 hr ( late ) of index culture Outcome Early CAZ AVI (n = 45) Late CAZ/AVI (n = 70) P Value Clinical success, n (%) 35 (78) 42 (60) .048 Median hospital LOS, days (IQR) 15 (7-27) 32 (17-53) <.001 Median ICU LOS, days (IQR) 9 (4-16) 16 (13-43) <.001 Treatment-emergent CZA resistance, n (%) 8 (11) <.001 Stone. J Antimicrob Chemother. 2018;73:2519. Coyne. ECCMID 2023. Abstr P2270.

41. Ceftolozane/Tazobactam vs Ceftazidime/Avibactam for MDR P. aeruginosa Retrospective, multicenter study comparing C/T vs CAZ/AVI in 200 patients with MDR P. aeruginosa infections in Saudi Arabia (N = 200) Overall baseline characteristics: Mean age 60 yr; 56% ICU, APACHE II 20 Site of infection: HAP/VAP ~50%, wound 24%, UTI ~10% Combination therapy more common in C/T arm (47% vs 35%; P = .08) Almangour. Antimicrob Agents Chemother. 2023;e0040523. Outcome, % C/T (n = 100) CAZ/AVI (n = 100) OR (95% CI) Clinical cure 61 66 0.81 (0.43-1.49) 30-day mortality 27 23 1.24 (0.65-2.35)

42. CACTUS: Ceftazidime/Avibactam vs Ceftolozane /Tazobactam for MDR P. aeruginosa in US Preliminary results from retrospective, matched cohort multicenter study; treated >48 hr within 7 days of index culture (blood or respiratory) Primary endpoint: clinical success (survival, no treatment extension or infection recurrence) Baseline characteristics: 82% in ICU; 74% on MV; ~1/3 on RRT; 84% with pneumonia C/T arm: more likely to receive prolonged infusion and suboptimal dosing regimens Rate, % Shields. IDWeek 2023. Abstr 1109. P = .30 P = .89

43. Imipenem/Cilastatin/Relebactam for CRPA RESTORE-IMI-1: multicenter, randomized phase III study comparing IMI/REL vs COL + IMI in patients with IMI-nonsusceptible bacterial infections (N = 47) 77% had CRPA 28-day all-cause mortality in mMITT population (n = 31): 9.5 % IMI/REL ; 30% COL + IMI AKI rates: 10% (3/29) IMI/REL ; 56% (9/16) COL + IMI ( P = .002) Motsch. Clin Infect Dis. 2020;70:1799. Clinical Response, mMITT population (%) Limited comparative studies available

44. Susceptibility Against Nonsusceptible P. aeruginosa Resistant Phenotype (n) Susceptibility, % Criteria Cefepime Ceftolozane/ Tazobactam Ceftazidime/ Avibactam Cefiderocol Meropenem nonsusceptibility (1759) 49 76.1 75.0 99.8 Ceftazidime/avibactam nonsusceptibility (477) 5.5 24.3 -- 100 Ceftolozane/tazobactam nonsusceptibility (463) 9.1 -- 22.0 99.8 Karlowsky. Antimicrob Agents Chemother. 2022;66:e0199021.

45. Limited comparative studies available CREDIBLE-CR 1 : randomized phase III trial in patients receiving cefiderocol vs BAT with nosocomial pneumonia, BSI, sepsis, or cUTI due to CR gram-negative organisms (N = 118)   CRPA: 12/80 (15%) patients received cefiderocol and 10/38 (26%) patients received BAT Similar all-cause mortality rates (without Acinetobacter spp) of 18% Similar clinical cure rates at test of cure ( cefiderocol : 58.3%; BAT : 50%) 2 PROVE 3 : multicenter, retrospective study evaluating patients receiving cefiderocol for gram-negative infections in US and EU In i nterim subgroup analysis of patients with P. aeruginosa infections (N=191), 83.2% isolates were carbapenem resistant (>90% cefiderocol susceptible) Clinical cure rate: 64.9%; 30-day all-cause mortality: 19.4% Cefiderocol for P. aeruginosa 1. Bassetti. Lancet Infect Dis. 2021;21:226. 2. Matsunaga. Open Forum Infect Dis. 2020;7:S212. 3. Larcher. ECCMID 2023. Abstr P2274.

46. Cefiderocol Compassionate Use for Resistant P. aeruginosa Infections Cefiderocol administered to 251 patients between 4/2016 to 11/2020 in US and EU; 46 patients with microbiologic and clinical data Satlin. Antimicrob Agents Chemother. 2023;67:e0019423. 12 10 8 6 4 2 No. of Isolates >64 Cefiderocol MIC (μg/mL) ≤0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 CLSI susceptibility breakpoint FDA susceptibility breakpoint 10 2 4 9 9 4 4 3 1 100 80 60 40 20 Clinical Response (%) 69 100 MICs 2-4 μg/mL MICs ≥8 μg/mL 9/13 4/4 100 80 60 40 20 Clinical Response (%) 69 76 MICs ≤1 μg/mL MICs >1 μg/mL 20/29 13/17

47. Challenges With Treating DTR- P. aeruginosa : How Do We Apply Antimicrobial Stewardship Principles? Newer agents often not on automated panels and may require send-out testing Comparator therapy often aminoglycosides and/or polymyxins Agents not compared with each other Retrospective cohort study bias Delays in Susceptibility Data Scant Clinical Data Genotypic susceptibility is challenging Risk factors poorly predictive Prediction of Resistance

48. Take-home Points: DTR- P. aeruginosa Resistance is complex and driven by various mechanisms (eg, porin reduction, β-lactamase, efflux pumps) Resistance to 1 β-lactam does not necessarily mean resistance to others Preferred treatment regimens include ceftolozane/tazobactam, ceftazidime/avibactam, or imipenem/cilastatin/relebactam Treatment challenges exist, such as difficulty predicting resistance, delays in susceptibility data, and limited prospective, comparative clinical data