New Antibiotic Approvals 2017-2019 Joshua Garcia, PharmD, BCPS Assistant Professor, Marshall B. Ketchum University May 12th 2020 Conflicts of Interest
No conflicts of interests to disclose Objectives
Identify indications for new, recently approved antimicrobials Recognize pros and cons of using newly approved antimicrobials in a clinical situation Identify major adverse effect, monitoring parameters, and clinical pearls of newly approved antimicrobials Antimicrobial Resistance Problem
Updated numbers: 2,800,000 illnesses and 35,000 deaths IDSA 10 x20 initiative
CDC Antimicrobial Resistance Reports, 2013 and 2019
GAIN Act – 2012
Limited Population Antibacterial Drug (LPAD) pathway 2016
Antibacterial Resistance Leadership Group of the National Institutes of Health (NIH)
Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) The Antibiotic Resistance Problem: The General Idea
Selective pressure (antibiotics) = Rise of resistant organisms
Wild-type bacteria Bacteria with resistance gene The Antibiotic Resistance Problem: The Macroscale
Selective pressures Inappropriate antibiotics
In the US: CDC estimated 30-50% (47 million courses) of all prescribed antibiotics are inappropriate / unnecessary Increasing use of broad spectrum antibiotics Antibiotic use in livestock and environment Dearth of new antimicrobials in development
1. Dellit TH, et al. Clin Infect Dis. 2007 Jan 15;44(2):159-77. 2. Fridkin SK, et al. MMWR Morb Mortal Wkly Rep. 2014;63(9):194-200 3. Fleming-Dutra KE, et al. JAMA. 2016 May 3;315(17):1864-73. doi: 10.1001/jama.2016.4151. 4. Woolhouse M, et al. Philos Trans R Soc Lond B Biol Sci. 2015 Jun 5; 370(1670): 20140083. doi: 10.1098/rstb.2014.0083 The Antibiotic Resistance Problem: The Microscale Antibiotic Inactivation Active Efflux
Ex. Beta-lacatamase production Ex. Tet(A) efflux pumps for tetracyclines
Porin Channel Target Alteration Degradation
Ex. OprD porin mutations in Pseudomonas aeruginosa Ex. mecA gene in MRSA Antibiotic Approval Timeline
Antibiotic Deployment
Antibiotic Resistance
Clatworthy et al. Nat Chem Biol. 2007 Sep;3(9):541-8 Antibiotic Approval Timeline: Updated
Antibiotic Deployment
Dalbavancin
Oritavancin
Tedizolid Avycaz Zerbaxa
2010 2015 2020
Antibiotic Resistance
Clatworthy et al. Nat Chem Biol. 2007 Sep;3(9):541-8 New Antibiotic Approvals: 2017-2019
Brand Name Generic Name Approval Date BaxdelaTM Delafloxacin 6/2017 VabormereTM Meropenem/vaborbactam 8/2017 ZemdriTM Plazomicin 7/2018 XeravaTM Eravacycline 8/2018 NuzyraTM Omadacycline 10/2018 RecarbrioTM Imipenem/cilastatin/relebactam 7/2019 XenletaTM Lefamulin 8/2019 Fetroja® Cefiderocol 11/2019 New Antibiotic Approvals by Intended Use / Indications
Acute Bacterial Skin and Skin Structure Infections (ABSSSI) Delafloxacin Resistant Gram Negative Bacilli Omadacycline Meropenem/vaborbactam Plazomicin Eravacycline Community Acquired Pneumonia (CAP) Imipenem/cilastatin/relebactam Omadacycline Cefiderocol Lefamulin Delafloxacin (BaxdelaTM) Delafloxacin (BaxdelaTM)
Indication: Acute bacterial skin and skin structure infections (ABSSSI) Spectrum of activity: Activity against S. pyogenes, S. pneumoniae, enteric gram negative rods, M. cattharalis, H. influenzae, B. fragilis, atypical organisms, S. aureus (including MRSA), and P. aeruginosa Mechanism of action: Enhanced inhibition of DNA gyrase and topoisomerase IV due to addition of chlorine at C-8 and removal of basic group at C-7 Dosing: PO: 450mg twice daily IV: 300mg every 12 hours Renal impairment:
PO: No adjustment
IV: eGFR 15-29 – 200mg every 12 hours
Not recommended in ESRD
1. Baxdela [package insert]. 2017 2. Mogle BT, et al. Journal of Antimicrobial Chemotherapy. 2018;73(6):1439-1451. doi:10.1093/jac/dkx543 Delafloxacin (BaxdelaTM)
Metabolism Negligible Elimination IV: 65% urine, 28% feces PO: 50% urine, 48% feces Half-life 4.2 – 8.5 hours
ADRs:
Common: Nausea, diarrhea, vomiting, headache, transaminase elevations
FQ Black boxed warnings: Tendon rupture, peripheral neuropathy, CNS effects, exacerbation of myasthenia gravis, hypoglycemia, AMS, aortic dissection Drug Interactions :
Oral chelation with cations
1. Baxdela [package insert]. 2017 2. Mogle BT, et al. Journal of Antimicrobial Chemotherapy. 2018;73(6):1439-1451. doi:10.1093/jac/dkx543 Delafloxacin Clinical Trials
Trial 1 (IV only) Trial 2 (IV to PO) Design Phase 3, multi-center, double-blind, randomized, non-inferiority Intervention • Delafloxacin 300mg IV BID • Delafloxacin 300mg IV BID for 3 • Vancomycin 15mg/kg + days, then switch to 450mg PO BID aztreonam 2g IV BID • Vancomycin 15mg/kg + aztreonam 2g IV BID Primary Efficacy Objective response at 48-72 hrs / clinical cure Outcome Exclusions Previous ABSSI antibiotic Pregnant or lactating Deeper tissue infection (bone, joint, etc.) or shock Immunocompromised ESRD or liver dysfunction > 10% body burns
1. Pullman J, et al. J Antimicrob Chemother. 2017;72(12):3471-3480. doi:10.1093/jac/dkx329 2. O’Riordan W, et al. Clin Infect Dis. 2018;67(5):657-666. doi:10.1093/cid/ciy165 Trial 1 Delafloxacin Efficacy Results Trial 2
1. Pullman J, et al. J Antimicrob Chemother. 2017;72(12):3471-3480. doi:10.1093/jac/dkx329 2. O’Riordan W, et al. Clin Infect Dis. 2018;67(5):657-666. doi:10.1093/cid/ciy165 S. Aureus Response Comparison
Trial 1
Trial 2
1. Pullman J, et al. J Antimicrob Chemother. 2017;72(12):3471-3480. doi:10.1093/jac/dkx329 2. O’Riordan W, et al. Clin Infect Dis. 2018;67(5):657-666. doi:10.1093/cid/ciy165 3. McCurdy S, Lawrence L, Quintas M, et al. Antimicrob Agents Chemother. 2017;61(9):e00772-17, e00772-17. doi:10.1128/AAC.00772-17 Trial 1 Delafloxacin Safety Results Trial 2
• No FQ related C. diff infections, tendon • 1 FQ related C. diff infection (delafloxacin), rupture, or peripheral neuropathy, tendon rupture, or peripheral neuropathy photosensitivity, or Qt prolongation • No tendon rupture, or peripheral neuropathy, • Equal delafloxacin hypo(hyper)glycemia photosensitivity, Qt prolongation or and vancomycin/aztreonam dysglycemia in either group
1. Pullman J, et al. J Antimicrob Chemother. 2017;72(12):3471-3480. doi:10.1093/jac/dkx329 2. O’Riordan W, et al. Clin Infect Dis. 2018;67(5):657-666. doi:10.1093/cid/ciy165 A Deeper Look into Safety
Photosensitivity Qtc Prolongation
1. Litwin JS, et al. Antimicrob Agents Chemother. 2015;59(6):3469-3473. doi:10.1128/AAC.04813-14 2. Dawe RS, et al. Photochem Photobiol Sci. 2018;17(6):773-780. doi:10.1039/C8PP00019K Delafloxacin Takeaways / Potential Places in Therapy
Takeaways:
Unique coverage of both Pseudomonas aeruginosa AND MRSA
Less likely to use as routine ABSSSI
No labeled warnings/adverse affects of Qt prolongation or photosensitivity Potential Places in Therapy:
Step down oral therapy for polymicrobial diabetic foot infections
Step down oral therapy for bloodstream infections
Community Acquired Bacterial Pneumonia (DEFINE-CABP) Omadacycline (NuzyraTM) Omadacycline (NuzyraTM)
Indication: Community acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) Spectrum of activity: Streptococcus, E. faecalis, E. faecium, S. aureus (MSSA and MRSA), B. fragilis, atypical organisms, M. cattharalis, H. influenzae
Potential coverage of vancomycin-resistant enterococci (VRE), Acinetobacter spp., and ESBL (extended-spectrum beta-lacatamase) producing organisms Mechanism of action: Aminomethyl group modification at C-9 allows for sustained protein synthesis inhibition in the presence of tetracycline efflux pumps Dosing:
IV Load
PO Load
1. Nuzyra [package insert]. 2018 2. Barber KE, et al. Pharmacotherapy. 2018;38(12):1194-1204. doi:10.1002/phar.2185 Omadacycline (NuzyraTM)
Metabolism Negligible Elimination 27% urine, 73% feces Half-life ~16 hrs at steady state
ADRs: Nausea, vomiting, diarrhea, transaminase elevations, hypertension Drug Interactions:
Anticoagulants: Depression of prothrombin activity may require dose decrease of anticoagulants
Oral chelation with cations
1. Nuzyra [package insert]. 2018 2. Barber KE, et al. Pharmacotherapy. 2018;38(12):1194-1204. doi:10.1002/phar.2185 Omadacycline Clinical Trials
OPTIC Trial (PNA) OASIS-1 (ABSSSI, IV-PO) OASIS-2 (ABSSSI, PO Only) Design Phase 3, multi-center, double-blind, randomized, non-inferiority Intervention • Omadacycline 100mg IV BID x2 • Omadacycline 100mg IV BID x2 • Omadacycline 450mg PO doses, then 100mg IV daily doses, then 100mg IV daily BID for 2 days, then 300mg (optional transition to 300mg PO (optional transition to 300mg PO daily after 3 days) PO after 3 days) • Linezolid 600mg PO BID • Moxifloxacin 400mg IV daily • Linezolid 600mg IV BID (optional switch to 400mg PO (optional transition to 600mg after 3 days) PO BID after 3 days) Primary Efficacy • Early clinical response (72 – 120 Early clinical response (20% reduction in lesion size at 48 – 72 hours Outcome hours after first dose) after first dose) Exclusions • Previous antibiotic in last 72 hrs Previous antibiotic in last 72 hrs • Hospital acquired PNA Skin lesions < 75cm2 • PSI class V patients Anticipated treatment > 14 days • Renal or hepatic insufficiency Chronic wounds, bites, or diabetic foot infections • Immunocompromised Renal or hepatic insufficiency Immunocompromised
1. Stets R, et al. N Engl J Med. 2019;380(6):517-527. doi:10.1056/NEJMoa1800201 2. O’Riordan W, et al. N Engl J Med. 2019;380(6):528-538. doi:10.1056/NEJMoa1800170 3. O’Riordan W, et al. Lancet Infect Dis. 2019;19(10):1080-1090. doi:10.1016/S1473-3099(19)30275-0 Omadacycline Efficacy Results OPTIC
Moxifloxacin better
OASIS-1 OASIS-2
1. Stets R, et al. N Engl J Med. 2019;380(6):517-527. doi:10.1056/NEJMoa1800201 2. O’Riordan W, et al. N Engl J Med. 2019;380(6):528-538. doi:10.1056/NEJMoa1800170 3. O’Riordan W, et al. Lancet Infect Dis. 2019;19(10):1080-1090. doi:10.1016/S1473-3099(19)30275-0 Omadacycline Safety Results
OPTIC Trial (PNA) OASIS-1 (ABSSSI, IV-PO) OASIS-2 (ABSSSI, PO Only) Similar ADR rate between overall Similar ADR rate between overall Slightly higher ADR rate in omadacycline (157, 41.1%) and omadacycline (156, 48.3%) and omadacycline (n=197, 54%) vs. moxifloxacin (188, 48.5%) linezolid (147, 45.7%) linezolid (n=137, 37%) Less diarrhea in omadacycline GI ADRs most common among Nausea more common with group (n=4, 1%) vs. moxifloxacin both omadacycline and linezolid omadacycline group (n=111, 30%) (n=31, 8%) groups (n=58, 18% and n=51, vs. linezolid group (n=8, 8%) 15.8%, respectively) • More common in loading phase No cases of C. difficile infection No cases of C. difficile infection No cases of C. difficile infection in omadacycline group (1 in Moxifloxacin group)
1. Stets R, et al. N Engl J Med. 2019;380(6):517-527. doi:10.1056/NEJMoa1800201 2. O’Riordan W, et al. N Engl J Med. 2019;380(6):528-538. doi:10.1056/NEJMoa1800170 3. O’Riordan W, et al. Lancet Infect Dis. 2019;19(10):1080-1090. doi:10.1016/S1473-3099(19)30275-0 Potential Considerations for Omadacycline Potential use in resistant nontuberculosis mycobacterium (NTM) infections Mycobacterium abscessus
In vitro activity
Promising MICs similar to tigecycline or amikacin
1. Bax HI, et al. Journal of Antimicrobial Chemotherapy. 2019;74(10):2930-2933. doi:10.1093/jac/dkz267 2. Shoen C, et al. Antimicrob Agents Chemother. 2019;63(5):e02522-18, /aac/63/5/AAC.02522-18.atom. doi:10.1128/AAC.02522-18 3. Minhas R, et al. Cureus. July 2019. doi:10.7759/cureus.5112 Omadacycline Takeaways / Potential Places in Therapy
Takeaways:
Good spectrum of activity compared to other tetracyclines
Be aware of differences in dosing differences in PO vs IV formulations and load vs maintenance dose regimens
Relatively mild ADRs with little clinical resistance or C. difficile infections reports Potential Places in Therapy:
Alternative agent for CABP (non-critically ill) or ABSSSI in multiple drug allergies and alternative to fluoroquinolones
Potential future use in non-TB mycobacterium infections Lefamulin (XenletaTM) Lefamulin (XenletaTM) Info
Indication: CABP Spectrum of activity: Streptococcus spp., S. aureus (including MRSA), E. faecium (including VRE), H. influenzae, M. catarrhalis, atypicals No activity for enteric gram negatives or E. faecalis Mechanism of action: Protein inhibition by binding to Peptidyl Transferase Center of 50s ribosome Dosing: IV: 150mg BID PO: 600mg BID Hepatic impairment (CP B or C)
Tablet not recommended
IV frequency should be changed to daily
1. Xenleta [package insert]. 2019 2. XENLETATM (lefamulin) Novel MOA. XENLETATM (lefamulin) Website for Healthcare Professionals. https://www.xenleta.com/novel-mechanism-of-action. Accessed March 28, 2020. Lefamulin (XenletaTM) Info
Metabolism CYP3A4 substrate Elimination Primarily excreted via feces Half-life ~8 hours
ADRs:
Qtc prolongation, embryo-fetal toxicity, C. difficile associated diarrhea Drug Interactions
Strong CYP3A4 of P-gp inducers and inhibitors (ie. rifampin and azole antifungals, respectively
No clinically significant interaction with other CYP3A4 or P-gp substrates
Class IA or Class III antiarrhythmic agents
1. Xenleta [package insert]. 2019 2. XENLETATM (lefamulin) Novel MOA. XENLETATM (lefamulin) Website for Healthcare Professionals. https://www.xenleta.com/novel-mechanism-of-action. Accessed March 28, 2020. Lefamulin Clinical Trials LEAP 1 (IV-PO) LEAP 2 (PO Only) Design Phase 3, multi-center, double-blind, randomized, non-inferiority Intervention • Lefamulin 150mg IV Q12h • Lefamulin 600mg PO Q12h for 5 days • Moxifloxacin 400mg IV Q24h • Moxifloxacin 400mg PO Q24h for 7 (+linezolid if MRSA suspected at days screening) • Optional switch to oral on day 3, total 7 days of treatment Primary Efficacy Early clinical response at 96 + 24 hours after first dose Outcome Exclusions • PORT Risk class < III • PORT Risk Class < II • Prior antibiotics • Prior antibiotics • Nursing home / long-term facility • Confirmed or suspected MRSA residence • Nursing home / long-term facility • Hospitalization w/in 90 days residence • Severe renal or hepatic dysfunction • Hospitalization w/in 90 days • Immunosuppressed • Severe renal or hepatic dysfunction
1. File TM, etal. Clin Infect Dis. 2019;69(11):1856-1867. doi:10.1093/cid/ciz090 2. Alexander E, et al. JAMA. September 2019. doi:10.1001/jama.2019.15468 Lefamulin Efficacy Data
LEAP 1
LEAP 2
1. File TM, etal. Clin Infect Dis. 2019;69(11):1856-1867. doi:10.1093/cid/ciz090 2. Alexander E, et al. JAMA. September 2019. doi:10.1001/jama.2019.15468 Lefamulin Safety Results
LEAP 1 LEAP 2 Similar ADR rate between overall lefamulin Overall ADR rate was higher in lefamulin (n=120, (n=104,38.1%) and moxifloxacin (n=103, 37.7%) 32.6%) vs. moxifloxacin (n=92, 25%) Lefamulin most common were hypokalemia, GI ADRs most common among both groups, but nausea, insomnia, and infusion site pain (all higher in lefamulin group (n=76, 15.76%) vs. 2.9%). Moxifloxacin was diarrhea at 7.7% moxifloxacin (n=14, 3.8%) No C. difficile rates reported 1 case of C. difficile infection reported in the lefamulin group Nonserious QTc prolongation rate and increase Qtc prolongation change from baseline was similar (lefamulin = 3, moxifloxacin = 5) 9.5ms in lefamulin and 11.6ms in moxifloxacin group
1. File TM, etal. Clin Infect Dis. 2019;69(11):1856-1867. doi:10.1093/cid/ciz090 2. Alexander E, et al. JAMA. September 2019. doi:10.1001/jama.2019.15468 Lefamulin Takeaways / Potential Places in Therapy
Takeaways:
Unique class of antibiotics for humans (pleuromutilins)
Indicated for Community Acquired Bacterial Pneumonia with activity for resistant gram positive infections
GI related ADRs may be worse than fluoroquinolone comparators, but QTc prolongation roughly the same Potential Places in Therapy:
Alternative agent to fluoroquinolone therapy for CABP in multiple drug allergies or resistances to first line options
One medication step down to oral therapy Meropenem/vaborbactam (VabomereTM) Meropenem/vaborbactam (VabomereTM) Info Indication: Complicated Urinary Tract Infections (cUTI) Spectrum of activity: Streptococcus spp., MSSA, B. fragilis, enteric gram negative rods, P. aeruginosa, A. baumannii, ESBL producing organisms, CRE (carbapenem resistant enterobaceriaceae) including Klebsiella pneumoniae carbapenemase (KPC) Does not expand activity against meropenem-resistant Acinetobater spp., P. aeruginosa, or S. maltophila isolates Mechanism of action: Meropenem – inhibits transpeptidase necessary for bacterial cell wall synthesis Vaborbactam – Boronic, Non-suicidal substrate that prevents meropenem degradation by beta- lactamses Gains activity against Ambler Class A (ESBLs and KPC) and Class C (AmpC beta-lacatamases)
1. Vabomere [package insert]. 2017 2. XENLETATM (lefamulin) Novel MOA. XENLETATM (lefamulin) Website for Healthcare Professionals. https://www.xenleta.com/novel-mechanism-of-action. Accessed March 28, 2020. 3. Tsivkovski R, et al. Antimicrob Agents Chemother. 2019;64(2):e01935-19, /aac/64/2/AAC.01935-19.atom. doi:10.1128/AAC.01935-19 Meropenem/vaborbactam (VabomereTM) Info
Dosing: All doses are administered over 3 hours eGFR > 50ml/min: 4g (2g meropenem + 2g vaborbactam) IV Q8h eGFR 30-49ml/min: 2g (1g meropenem + 1g vaborbactam) IV Q8h eGFR 15-29ml/min: 2g (1g meropenem + 1g vaborbactam) IV Q12h eGFR < 15ml/min: 1g (0.5g meropenem + 0.5g vaborbactam) IV Q12h
Metabolism 22% meropenem hydrolysis, none for vaborbactam Elimination Primarily excreted in urine Half-life ~1.22 hrs meropenem, ~1.68 hrs vaborbactam
ADRs: Meropenem related hypersensitivity, seizure threshold reduction, C. difficile infection, thrombocytopenia, and neuromotor impairment Drug Interactions: Reduction in valproic acid concentrations Probenecid may increase serum meropenem concentrations
1. Vabomere [package insert]. 2017 2. XENLETATM (lefamulin) Novel MOA. XENLETATM (lefamulin) Website for Healthcare Professionals. https://www.xenleta.com/novel-mechanism-of-action. Accessed March 28, 2020. 3. Tsivkovski R, et al. Antimicrob Agents Chemother. 2019;64(2):e01935-19, /aac/64/2/AAC.01935-19.atom. doi:10.1128/AAC.01935-19 Meropenem/vaborbactam Clinical Trials TANGO 1 (cUTI) TANGO 2 (CRE Infections - cUTI/AP, HABP, VABP, cIAI, bacteremia) Design Phase 3, multi-center, double-blind, randomized, Phase 3, multi-center, open-label, randomized, active-controlled non-inferiority Intervention • Meropenem/vaborbactam (2g/2g) IV Q8h over 3 • Meropenem/vaborbactam (2g/2g) IV Q8h over 3 hours for 7-14 hours days • Piperacillin/tazobactam (4g/0.5g) IV Q8h over • Best available therapy (BAT) for 7-14 days 30 mins o Combination or monotherapies: Polymyxins, carbapenems, • After 15 doses, both groups could switch to aminoglycosides, tigecycline levofloxacin 500mg PO daily to finish 10 day o Monotherapy: Ceftazidime/avibactam course Primary • Overall: Clinical Cure at End of Therapy (EOT) and Test of Cure Efficacy (TOC) in mCRE-MITT population • cUTI/AP: Clinical cure + microbiological eradication Composite overall success at end of IV therapy: Outcome • HABP/VABP: All-cause mortality • Clinical cure / improvement • Bacteremia: All-cause mortality • Microbiological eradication • cIAI: Proportion of patients with clinical cure • All endpoints evaluated at Test of Cure (TOC) = 7 + 2 days after treatment Exclusions • Prior antibiotics • Confirmed New Delhi Metallo- (NDM), Verona Integrin-encoded • Immunocompromised Metallo- (VIM), Imipenemase Metallo-, or Oxacillinase encoded • Sepsis or septic shock (OXA) beta-lactamases • Perinephric abscess, kidney transplant, • Acute Physiology and Chronic Health Evaluation II Score > 30 hemodialysis, or other renal complication • Immediately life threatening illness • Recent urinary tract surgery • CRRT
1. Kaye KS, et al. JAMA. 2018;319(8):788-799. doi:10.1001/jama.2018.0438 2. Wunderink RG, et al. Infect Dis Ther. 2018;7(4):439-455. doi:10.1007/s40121-018-0214-1 TANGO 2 More Information
MIC Distributions of Isolated Organisms Best Available Therapy (BAT) Options
Infection Types
1. Wunderink RG, et al. Infect Dis Ther. 2018;7(4):439-455. doi:10.1007/s40121-018-0214-1 Meropenem/vaborbactam Efficacy Results TANGO 1
TANGO 2
BAT arm stopped early due to interim analysis showing no additional risk-benefit, trial amended to single arm study
1. Kaye KS, et al. JAMA. 2018;319(8):788-799. doi:10.1001/jama.2018.0438 2. Wunderink RG, et al. Infect Dis Ther. 2018;7(4):439-455. doi:10.1007/s40121-018-0214-1 Meropenem/vaborbactam Safety Results
TANGO 1 TANGO 2 Similar ADR rate between overall Fewer severe, drug related, and over ADR with meropenem/vaborbactam (15.1%) and meropenem/vaborbactam vs. BAT (14% vs. 28%, piperacillin/tazobactam (12.8%) 24% vs. 44%, and 84% vs. 92%, respectively) Most common ADR in both groups was headache. Lower rates of renal ADRs in Majority of ADRs were mild to moderate meropenem/vaborbactam (n=2, 4%) vs. BAT (n=6, 24%) No C. difficile rates reported Nonserious QTc prolongation rate and increase similar (lefamulin = 3, moxifloxacin = 5)
1. Kaye KS, et al. JAMA. 2018;319(8):788-799. doi:10.1001/jama.2018.0438 2. Wunderink RG, et al. Infect Dis Ther. 2018;7(4):439-455. doi:10.1007/s40121-018-0214-1 Meropenem/vaborbactam Takeaways / Potential Places in Therapy
Takeaways:
Potential effective option for patients with resistant KPC cUTI, bacteremia, PNA, cIAI
Addition of vaborbactam does not restore susceptibility to Pseudomonas aeruginosa, Acinetobacter spp., or Stenotrophomonas maltophila isolates
Not effective against metallo-betalactamses or oxacillinases (OXA-28)
Infused over 3 hours Potential Places in Therapy:
Resistant KPC CREs infections in cUTIs and potentially, bacteremia, pneumonia, and intra-abdominial infections especially if concerned for renal toxicities
Not for carbapenem resistant Pseudomonas or Acinetobacter infections Plazomicin (ZemdriTM) Info Plazomicin (ZemdriTM) Info
Indication: cUTI (only) Spectrum of activity: Enterobaceriaceae
Activity against ESBLs, KPCs, and OXA-48 beta-lactmases
No activity against Acinetobacter spp., Stenotrophomonas spp., and NDM beta- lacatamase. Has variable activity against P. aeruginosa Mechanism of action: Inhibition of protein synthesis via 30s ribosomal subunit
Lack of 3’ and 4’ hydroxyl group prevents inactivation by aminoglycoside modifying enzymes. Hydroxyl‐aminobutyric acid group at position 1 and hydroxyethyl group at the 6′ position provides additional spectrum of activity Dosing: Dosing based on total body weight (adjusted if TBW > 25% IBW)
CrCl > 60mL/min: 15mg/kg IV Q24h
CrCl 30-59mL/min: 10mg/kg IV Q24h
CrCl 15-29mL/min: 10mg/kg IV Q48h
1. Zemdri [package insert]. 2018 2. Shaeer KM, et al. Pharmacotherapy. 2019;39(1):77-93. doi:10.1002/phar.2203 Plazomicin (ZemdriTM) Info
Therapeutic Drug Monitoring: Recommended for CrCl 15-90ml/min to maintain trough concentrations < 3mcg/mL
Measure plazomicin trough concentration 30mins before second dose
If level > 3mcg/mL, increase dosing frequency by 1.5x (ie. 24hrs -> 36hrs)
Metabolism Negligible Elimination Primarily excreted in urine Half-life 3.5 hrs ADRs: Decreased renal function, diarrhea, hypertension, headache, nausea, vomiting and hypotension
Aminoglycoside class warning: Nephrotoxicity, ototoxicity, neuromuscular blockade, and fetal harm Drug Interactions: No major interactions observed yet
1. Zemdri [package insert]. 2018 2. Shaeer KM, et al. Pharmacotherapy. 2019;39(1):77-93. doi:10.1002/phar.2203 Plazomicin Clinical Trials
EPIC Trial (cUTI) CARE Trial (CRE BSI/HABP/VAP) Design Phase 3, multi-center, double-blind, randomized, Phase 3, multicenter, open-label, randomized, descriptive non-inferiority Intervention • Plazomicin 15mg/kg IV Q24h Cohort 1: • Meropenem 1g IV Q8h • Plazomicin 15mg/kg IV Q24h + meropenem or tigecycline • After 4 days, both groups could switch to • Colistin base 5mg/kg IV Q24h + meropenem or tigecycline levofloxacin 500mg PO daily to finish 7-10 day Cohort 2: course • Plazomicin 15mg/kg IV Q24h + investigators choice for 7-14 days (BSI or HABP/VAP) or 4-7 days (cUTI) Primary Composite cure at day 5 and TOC (15-19 days after Composite death from any cause at day 28 or significant disease Efficacy initiation) in m-MITT population: related complication in the m-MITT population • Clinical cure / improvement Outcome • Microbiological eradication Exclusions • Prior antibiotics • Prior antibiotics (> 96 hours prior to starting study regimen) • Immunocompromised • Known colistin resistance • Sepsis or septic shock • Pulmonary or renal obstruction • Perinephric abscess, kidney transplant, • Acute renal failure or HD at randomization hemodialysis, or other renal complication • BSI: Source unremovable within 4 days • Recent urinary tract surgery • Anticipated therapy > 14 days • Pathogen resistant to meropenem
1. Wagenlehner FME, et al. N Engl J Med. 2019;380(8):729-740. doi:10.1056/NEJMoa1801467 2. McKinnell JA, et al. N Engl J Med. 2019;380(8):791-793. doi:10.1056/NEJMc1807634 Plazomicin Efficacy Results CARE Trial
EPIC Trial
1. Wagenlehner FME, et al. N Engl J Med. 2019;380(8):729-740. doi:10.1056/NEJMoa1801467 2. McKinnell JA, et al. N Engl J Med. 2019;380(8):791-793. doi:10.1056/NEJMc1807634 Plazomicin Safety Results CARE Trial
EPIC Trial Similar ADR rate between overall plazomicin (19.5%) and meropenem (21.6%) Most common ADRs in plazomicin group: decreased renal function, diarrhea, hypertension, headache, nausea, vomiting and hypotension all at 1-3%
Higher rates of renal function ADRs in plazomicin group (n=11, 3.6%) vs. meropenem group (n=4, 1.3%) Each group had 1 patient with cochlear / vestibular ADRs
1. Wagenlehner FME, et al. N Engl J Med. 2019;380(8):729-740. doi:10.1056/NEJMoa1801467 2. McKinnell JA, et al. N Engl J Med. 2019;380(8):791-793. doi:10.1056/NEJMc1807634 Plazomicin and the CARE Trial Difficulties
Although the FDA Antimicrobial Drugs Advisory Committee voted to approve plazomicin for the cUTI indication, the panel voted against approving for the indication for bloodstream infections Difficulty enrolling patients in the CARE trial led to numerous protocol changes (combined 39 patients) Various methodological questions concerning plazomicin role in positive clinical outcomes
Only 1 positive blood culture needed for inclusion
Large inclusion time (96 hours) for empiric treatment before randomization
Improvement in two plazomicin patients with only one day of therapy before polymyxin switch
1. Wagenlehner FME, et al. N Engl J Med. 2019;380(8):729-740. doi:10.1056/NEJMoa1801467 2. McKinnell JA, et al. N Engl J Med. 2019;380(8):791-793. doi:10.1056/NEJMc1807634 Plazomicin Takeaways / Potential Places in Therapy
Takeaways:
Plazomicin is a novel aminoglycoside with activity against resistant gram negative enterobaceriaceae (including CRE)
Trough recommended to be taken prior to second dose and should be < 3 mcg/mL (if higher increase frequency x1.5)
Plazomicin did not receive FDA approval for bloodstream infections due to lack of enrollment causing protocol issues Potential Places in Therapy:
cUTI infections caused by MDR enterobaceriaceae (more data needed for BSI and pneumonia) Eravacycline (XeravaTM) Eravacycline (XeravaTM) Info
Indication: Complicated intra-abdominal infections (cIAI) Spectrum of activity: Similar to tigecycline
Covers enteric gram negative rods, S. aureus (including MRSA), B. fragilis, Enterococcus spp. (including VRE), CREs, and Acinetobcater spp.
Lacks activity against P. aeruginosa Mechanism of action: Fluorocycline that inhibits 30s ribosomal subunit for bacterial protein synthesis Dosing: 1mg/kg IV Q12h over 60 mins
Child-Pugh C: 1mg/kg IV Q12h on day 1, then 1mg/kg IV Q24h
Doses based on total body weight
1. Xerava [package insert]. 2018 2. Zhanel GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs. 2016;76(5):567-588 Eravacycline (XeravaTM) Info
Metabolism CYP3A4 and FMO mediated oxidation Elimination 34% excreted in urine, 47% in feces Half-life 20 hrs
ADRs
Infusion site reactions, nausea, vomiting, diarrhea, C. difficile infection
Tetracycline class warnings: Tooth discoloration, bone growth inhibition, photosensitivity Drug Interactions
CYP3A4 inducers: Decrease exposure to eravacycline. Increase dose to 1.5mg/kg IV Q12h
Anticoagulants: Depression of prothrombin activity may require dose decrease of anticoagulants
1. Xerava [package insert]. 2018 2. Zhanel GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs. 2016;76(5):567-588 Eravacycline Clinical Trials
IGNITE 1 (cIAI) IGNITE 4 (cIAI)
Design Phase 3, multi-center, double-blind, Phase 3, multi-center, open-label, randomized, active- randomized, non-inferiority controlled Intervention • Eravacycline 1mg/kg IV q12h • Eravacycline 1mg/kg IV q12h • Ertapenem 1g IV Q24h • Meropenem 1g IV Q8h Primary • Clinical response: Complete resolution or • The primary endpoint was the clinical response at Efficacy significant improvement of signs or the TOC visit 25–31 days after initiation of the study symptoms of the index infection such that drug Outcome no additional antibacterial therapy, surgical, or radiological intervention was required Exclusions • Rapidly progressing / immediately life- • Rapidly progressing / immediately life-threatening threatening disease disease • Septic shock • Septic shock • Possible signs of significant hepatic disease • Possible signs of significant hepatic disease • CrCl < 50mL/min • CrCl < 50mL/min • Complicated appendicitis • Complicated appendicitis • Prior antibiotic • Prior antibiotic • 50% appendectomy patients
1. Solomkin JS, et al. JAMA Surg. 2017;152(3):224-232. doi:10.1001/jamasurg.2016.4237 2. Solomkin JS, et al. Clin Infect Dis. 2019;69(6):921-929. doi:10.1093/cid/ciy1029 Eravacycline Efficacy Results IGNITE 4 IGNITE 1
One KPC-2 and one OXA-48 were identified and treated in the meropenem group 1. Solomkin JS, et al. JAMA Surg. 2017;152(3):224-232. doi:10.1001/jamasurg.2016.4237 2. Solomkin JS, et al. Clin Infect Dis. 2019;69(6):921-929. doi:10.1093/cid/ciy1029 Eravacycline Safety Results
IGNITE 1 IGNITE 4 More ADRs in the eravacycline (n=113, More ADRs in the eravacycline (n=93, 41.8%) compared to ertapenem (n=75, 32.7%) compared to meropenem (n=77, 28%) 30.9%) Eravacycline had more nausea and Highest eravacycline ADRs were phlebitis as compared to ertapenem gastrointestinal disorders such as (8.1% vs. 0.7% and 3% vs. 0.4%, nausea (n = 12), respectively) vomiting (n = 9), and diarrhea (n = 6)
1. Solomkin JS, et al. JAMA Surg. 2017;152(3):224-232. doi:10.1001/jamasurg.2016.4237 2. Solomkin JS, et al. Clin Infect Dis. 2019;69(6):921-929. doi:10.1093/cid/ciy1029 What About IGNITE 2 and 3?
Phase 3, randomized, double blinded, non-inferiority trials evaluating eravacycline in cUTI
IGNITE 2: Eravacycline vs. levofloxacin
IGNITE 3: Eravacycline vs. ertapenem Both trials failed to meet non-inferiority
IGNITE 2: Proportion of participants demonstrating clinical cure / improvement
IGNITE 3: Proportion of participants with a responder outcome Eravacycline does not have an indication for cUTI
1. Tetraphase Announces Top-Line Results From IGNITE2 Phase 3 Clinical Trial of Eravacycline in cUTI. Tetraphase Pharmaceuticals. https://ir.tphase.com/news-releases/news-release-details/tetraphase-announces-top-line-results- ignite2-phase-3-clinical. Accessed March 30, 2020. 2. Tetraphase Announces Top-Line Results from IGNITE3 Phase 3 Clinical Trial of Eravacycline in Complicated Urinary Tract Infections (cUTI). Tetraphase Pharmaceuticals. https://ir.tphase.com/news-releases/news-release- details/tetraphase-announces-top-line-results-ignite3-phase-3-clinical. Accessed March 30, 2020. 3. Efficacy and Safety Study of Eravacycline Compared With Levofloxacin in Complicated Urinary Tract Infections - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01978938. Accessed March 30, 2020. 4. Efficacy and Safety Study of Eravacycline Compared With Ertapenem in Participants With Complicated Urinary Tract Infections - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03032510. Accessed March 30, 2020. Eravacycline Takeaways / Potential Places in Therapy
Takeaways:
Spectrum of activity is comparable to tigecycline
Activity against CRE and Acinetobacter spp., but lacks P. aeruginosa activity
Most common ADR are GI-related but tend to be less frequent than tigecycline Potential Places in Therapy:
Potential substitute for tigecycline therapy in an MDR patient that cannot tolerate tigecycline-related GI ADRs
Eravacycline should not be used in cUTI or acute pyelonephritis cases Imipenem/cilastatin/relebactam (RecarbrioTM) Imipenem/cilastatin/relebactam (RecarbrioTM) Info
Indication: cUTI and cIAI Spectrum of activity: Same as imipenem/cilistatin but with added CRE activity (Ambler Class A and C) Restores lost P. aeruginosa activity lost to imipenem from AmpC Mechanism of action: Relebactam forms initial non-covalent association with a susceptible β-lactamase binding site followed by a covalent acylation at the β- lactamase serine residue, protecting imipenem from degredation Dosing: 1.25g (500mg imipenem, 500mg cilastatin, 250mg relebactam) IV Q6h CrCl 60-89: 1g (400mg/400mg/200mg) IV Q6h CrCl 30-59: 0.75g (300mg/300mg/150mg) IV Q6h CrCl 15-29: 0.5g (200mg/200mg/100mg) IV Q6h ESRD or HD: 0.5g (200mg/200mg/100mg) IV Q6h timed to follow HD
1. Recarbrio [package insert]. 2019 2. Wong D, van Duin D. Drugs. 2017;77(6):615-628. doi:10.1007/s40265-017-0725-1 Imipenem/cilastatin/relebactam (RecarbrioTM) Info
Metabolism Negligible due to cilistatin Elimination Primarily urine Half-life 1-1.2 hrs ADRs
Hypersensitivity reactions, seizures / CNS ADRs, C. difficile infections Drug Interactions
Ganciclovir – Increased risk of seizures
Valproic acid – Decreased levels of valproic acid and increased seizure risk
1. Recarbrio [package insert]. 2019 2. Wong D, van Duin D. Drugs. 2017;77(6):615-628. doi:10.1007/s40265-017-0725-1 Imipinem/cilastatin/relebactam Clinical Trials
RESTORE-IMI 1 (IMI non-susceptible RESTORE-IMI 2 (HABP/VAP) HAP/VAP, cUTI, cIAI) Design Phase 3, multi-center, double-blind, Phase 3, multi-center, open-label, randomized, active- randomized, active controlled controlled Intervention • IMI/CIL/REL 1.25g IV Q6h • IMI/CIL/REL 1.25g IV Q6h + linezolid • Colistimethate sodium 150mg CBA IV q12h + • Piperacillin/tazobactam 4g IV Q6h + linzolid IMI/CIL 1g IV Q6h • Treatment duration 5 – 21 days • All cause mortality at through Day 28 Primary Overall response in mMITT: Efficacy • cUTI/AP: Clinical cure + microbiological Outcome eradication • HAP/VAP: 28 day all-cause mortality • cIAI: 28 day response
Exclusions • Resistant to relebactam or colistin • Gram positive infection • Susceptible to IMI alone • Confirmed of suspected CABP • APACHE Score > 30 • Immunosuppressed • ESRD • Seizure history • CrCl < 15mL/min • Life expectancy < 72 hours • Concomitant active antibiotics • Previous antibiotics • Pulmonary or urinary obstructions • Concomitant antiseizure medications
1. Motsch J, et al. Clin Infect Dis. August 2019. doi:10.1093/cid/ciz530 2. Pivotal RESTORE-IMI 2 Phase 3 Study of Merck’s RECARBRIOTM (imipenem, cilastatin, and relebactam) in Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (HABP/VABP) Met Primary Endpoint | Merck Newsroom Home. https://www.mrknewsroom.com/news-release/research-and-development-news/pivotal-restore-imi-2-phase-3-study-mercks-recarbrio-imip. Accessed March 30, 2020. 3. Imipenem/Relebactam/Cilastatin Versus Piperacillin/Tazobactam for Treatment of Participants With Bacterial Pneumonia (MK-7655A-014) - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02493764. Accessed March 30, 2020. Imipinem/cilistatin/relebactam Efficacy Results RESTORE-1
RESTORE-IMI 2 currently unavailable but MERCK news statement 9/30/19: “Results from the trial showed RECARBRIO met both the primary and key secondary endpoints of statistical non- inferiority compared to piperacillin/tazobactam in Day 28 all-cause mortality and clinical response at early follow up, respectively, in the modified intent-to-treat (MITT) population. Rates of adverse events observed in the trial were similar in both groups. Merck plans to present the full data from the trial at a scientific congress in 2020.”
1. Motsch J, et al. Clin Infect Dis. August 2019. doi:10.1093/cid/ciz530 2. Pivotal RESTORE-IMI 2 Phase 3 Study of Merck’s RECARBRIOTM (imipenem, cilastatin, and relebactam) in Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (HABP/VABP) Met Primary Endpoint | Merck Newsroom Home. https://www.mrknewsroom.com/news-release/research-and-development-news/pivotal-restore-imi-2-phase-3-study-mercks-recarbrio-imip. Accessed March 30, 2020. 3. Imipenem/Relebactam/Cilastatin Versus Piperacillin/Tazobactam for Treatment of Participants With Bacterial Pneumonia (MK-7655A-014) - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02493764. Accessed March 30, 2020. Imipinem/cilistatin/relebactam Safety Results
1. Motsch J, et al. Clin Infect Dis. August 2019. doi:10.1093/cid/ciz530 2. Pivotal RESTORE-IMI 2 Phase 3 Study of Merck’s RECARBRIOTM (imipenem, cilastatin, and relebactam) in Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (HABP/VABP) Met Primary Endpoint | Merck Newsroom Home. https://www.mrknewsroom.com/news-release/research-and-development-news/pivotal-restore-imi-2-phase-3-study-mercks-recarbrio-imip. Accessed March 30, 2020. 3. Imipenem/Relebactam/Cilastatin Versus Piperacillin/Tazobactam for Treatment of Participants With Bacterial Pneumonia (MK-7655A-014) - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02493764. Accessed March 30, 2020. Imipenem/cilastatin/relebactam Takeaways / Potential Places in Therapy
Takeaways:
Relebactam restores activity of imipenem lost due to beta-lactamase activity
Increased seizure potential reported with concomitant valproic acid (historical) and ganciclovir use (reported) Potential Places in Therapy:
Alternative to colistin therapy for multidrug resistant Pseudomonas aeruginosa infections or KPC CRE infections if wanting to preserve renal function Cefiderocol (FetrojaTM) Cefiderocol (FetrojaTM) Info
Indication: cUTI Spectrum of activity: Resistant Enterobaceriaceae, Acinetobacter baumannii, P. aeruginosa, and Stenotrophomonas maltophilia
Has activity against bacteria producing Ambler class A, B, C, and D beta-lactamases Mechanism of action: Functions as a siderophore, binding to extracellular free ferric iron. This allows for uptake across the outer cell membrane of bacteria into the periplasmic space Dosing: 2g IV Q8h over 3 hours
CrCl > 120mL/min: 2g IV Q6h over 3 hours
CrCl 30-59mL/min: 1.5g IV Q8h over 3 hours
CrCl 15-29mL/min: 1g IV Q8h over 3 hours
ESRD w/ or w/o HD: 0.75g IV Q12h over 3 hours
1. Fetroja [package insert]. 2019 2. Fetroja® (cefiderocol) | Official HCP Site | Now Available. https://www.fetroja.com. Accessed March 30, 2020. Cefiderocol (FetrojaTM) Info
Metabolism Negligible Elimination Primarily urine Half-life 2-3 hrs ADRs
Warning for increase in all-cause mortality in critically ill patients with multi-drug resistant gram-negative infections
Hypersensitivity reactions, C. difficile infections, seizures and other CNS adverse reactions Drug Interactions
May lead to false-positive results in dipstick tests (urine protein, ketones, or occult blood)
1. Fetroja [package insert]. 2019 2. Fetroja® (cefiderocol) | Official HCP Site | Now Available. https://www.fetroja.com. Accessed March 30, 2020. Cefiderocol Clinical Trials
APEKS-cUTI APEKS-NP CREDIBLE-CR (CRE HAP/VAP/HCAP, cUTI, BSI) Design Phase 2, multi-center, double- Phase 3, multi-center, double- Phase 3, multi-center, open- blind, randomized, non-inferiority blind, randomized, non-inferiority label, active controlled Intervention • Cefiderocol 2g IV Q8h • Cefiderocol 2g IV Q8h + • Cefiderocol 2g IV Q8h • Imipenem/cilistatin 2g (1g/1g) linezolid 600mg IV Q12h • BAT: Polymyxin or non- IV Q8h • Meropenem 2g IV Q8h + polymyxin-based regimen linezolid 600mg IV Q12h containing 1-3 antibiotics
Primary Efficacy Composite overall success at TOC: All-cause mortality at day 14 • Clinical cure at TOC: Outcome • Clinical cure / improvement HAP/VAP/HCAP or BSI • Microbiological eradication • Microbiologic eradication at TOC: cUTI Exclusions • Carbapenem-resistant • Known CABP, atypical PNA, • Coinfectoin with invasive mold infections viral PNA, or chemical PNA • Requiring > 3 weeks therapy • Polymicrobial infection or • Other treatment specific • Refractory septic shock Immunocompromised fungal UTI exclusion criteria • • APACHE score > 30 • CrCl < 20 mL/min • Peritoneal dialysis
1. Portsmouth S, et al. Lancet Infect Dis. 2018;18(12):1319-1328. doi:10.1016/S1473-3099(18)30554-1 2. Clinical Study of S-649266 for the Treatment of Nosocomial Pneumonia Caused by Gram-negative Pathogens - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03032380. Accessed March 30, 2020. 3. Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02714595. Accessed March 30, 2020. 4. Park F. ANTIMICROBIAL DRUGS ADVISORY COMMITTEE: CEFIDEROCOL BRIEFING DOCUMENT NDA # 209445. :375. Cefiderocol Efficacy Results APEKS-cUTI
APEKS-NP
CREDIBLE-CR
1. Portsmouth S, et al. Lancet Infect Dis. 2018;18(12):1319-1328. doi:10.1016/S1473-3099(18)30554-1 2. Clinical Study of S-649266 for the Treatment of Nosocomial Pneumonia Caused by Gram-negative Pathogens - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03032380. Accessed March 30, 2020. 3. Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02714595. Accessed March 30, 2020. 4. Park F. ANTIMICROBIAL DRUGS ADVISORY COMMITTEE: CEFIDEROCOL BRIEFING DOCUMENT NDA # 209445. :375. Cefiderocol Safety Results
CREDIBLE-CR
• The hazards ratio for time to death with 1.77, 95% CI (0.87–3.57), p-value of 0.11 • Greatest imbalance of death was at end of study with • A. baumannii infections (cefiderocol 19/39 (49%) vs BAT 4/17 (24%)) • APACHE II scores > 16 (cefiderocol 21/46 (46%) vs BAT 5/22 (23%))
4. Park F. ANTIMICROBIAL DRUGS ADVISORY COMMITTEE: CEFIDEROCOL BRIEFING DOCUMENT NDA # 209445. :375. Cefiderocol Takeaways / Potential Places in Therapy
Takeaways:
Cefiderocol is a cephalosporin with a novel iron-binding mechanism of action
Only antibiotic with activity against all Ambler class beta-lactamases
Clinical data currently shows mixed results, with CREDIBLE-CR study showing risk for increased mortality Potential Places in Therapy:
Resistant CRE infections in which other novel agents cannot be used / resistance has developed Comparison of Gram Negative Agents
Carbapenem Resistant Carbapenem Resistant Other Cases to Avoid Indications Pseudomonas Activity Acinetobacter Activity Use cUTI Ceftazidime / cIAI Potentially No avibactam HAP/VAP cUTI Ceftolozane / cIAI Yes No KPC or other CREs tazobactam HAP/VAP Meropenem / If Pseudomonas or vaborbactam cUTI No No Acinetobacter with resistance to meropenem BSI or HABP/VAP Plazomicin cUTI No No Resistant Pseuomonas Eravacycline cIAI No Yes cUTI or pyelo Imipenem/ cilistatin/ cUTI Yes No History of seizures relebactam cIAI If other new agents Cefiderocol cUTI Yes Yes* available *Although good in vitro activity, highest mortality differential noted in Acinetobacter spp. infections via CREDIBLE-CR Trial. More clinical data is needed Questions?