Antibiotics – an update on recently approved and investigational drugs Jenner Minto, Pharm.D. Disclosures
• Nothing to disclose Learning Objectives
• Describe the use of new antibacterial agents in clinical practice
• Describe the therapeutic potential of antibiotics currently in development Assessment Questions
1. Which of the following statements regarding new antibacterial agents is true? A. Most are FDA approved to treat a broad range of infections B. Recently approved antibiotics are likely to become first-line agents C. Many have a novel mechanism of action D. Most are reserved for infections caused by organisms that are resistant to existing antibiotics
2. The majority of antibiotics currently in development target which pathogen(s)? A. Gram-positive organisms B. Gram-negative ESKAPE pathogens C. Drug-resistant Neisseria gonorrheae D. Drug-resistant Clostridioides difficile Recently Approved Antibiotics 2018 Approvals Plazomicin (Zemdri®) Evracycline (Xerava®) Sarecycline (Seysara®) Omadacycline (Nuzyra®) Rifamycin (Aemcolo®)
2019 Approvals Imipenem, cliastatin, relebactam (Recabrio®) Pretomanid Lefamulin (Xenleta®) Cefiderocol (Fetroja®) Plazomicin (Zemdri®)
Approved • June, 2019
Indications • Complicated urinary tract infections (cUTIs), including pyelonephritis, caused by: E. coli, K. pneumoniae, P. mirabilis, Enterobacter cloacae
*Reserved for patients ≥ 18 years of age with limited or no alternative treatment options
https://zemdri.com/ https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf Plazomicin (Zemdri®)
Class • Aminoglycoside Mechanism of Action • Inhibits bacterial protein synthesis by binding the bacterial 30S ribosomal subunit Resistance • Aminoglycoside resistance results from production of aminoglycoside modifying enzymes (AMEs), alteration of ribosomal target, up-regulation of efflux pumps, and reduced permeability due to porin loss • Plazomicin is not inhibited by most AMEs that affect other aminoglycosides
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf Plazomicin (Zemdri®)
Spectrum of Activity
• Broad activity against β-lactamase and AME-producing Enterobacteriaceae Escherichia coli Klebsiella pneumoniae Proteus mirabilis Enterobacter Cloacae
• In vitro susceptibility with unknown clinical significance Citrobacter spp. Enterobacter aerogenes Klebsiella oxytoca Morganella morganii Proteus vulgaris Providencia stuartii Serratia marcescens
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf Plazomicin (Zemdri®)
Dosing and Administration Dose • 15mg/kg q24h over 30 minutes • Renal dose adjustment required
Duration • 4 to 7 days
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf Plazomicin (Zemdri®)
Warnings and Precautions • Nephrotoxicity • Ototoxicity • Neuromuscular Blockade • Fetal Harm • Hypersensitivity reactions • Clostridioides difficile-associated diarrhea • Development of Drug-Resistant Bacteria
Black Box Warnings • Nephrotoxicity • Ototoxicity Hearing loss, tinnitus, vertigo • Neuromuscular blockade • Fetal harm
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf Plazomicin (Zemdri®)
Adverse Reactions
• Decreased renal function (11%) • Diarrhea (7%) • Hypertension (7%) • Nausea/Vomiting (4%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf Plazomicin (Zemdri®)
Use in specific populations Pregnancy Use not recommended No available data
Lactation Insufficient data in humans Present in lactating rats, systemic exposure ~ 0.04% maternal exposure
Geriatric Use Higher rates of adverse reactions in patients ≥ 65 years 40% of patients in clinical trials were ≥ 65 years 17.2 % of patients in clinical trials were ≥ 75 years
Pediatric Use Safety and efficacy not established
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf Plazomicin (Zemdri®)
Clinical Trial Data Two comparator-controlled clinical trials in patients with cUTI, including pyelonephritis Compared to Meropenem Non-inferior Composite cure at day 5 (88% vs. 91.4%) Higher % of patients had microbiologic eradication at test-of-cure visit (81.7% vs. 70.1%) Small sample size (n=609)
Utility in clinical practice Limited by adverse effects and limited safety & efficacy data
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf
Eravacycline (Xerava®)
Approved • August, 2018
Indications
• Complicated intra-abdominal infections (cIAI)
*Reserved for patients ≥ 18 years of age with limited or no alternative treatment options
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf. Eravacycline (Xerava®)
Class
• Synthetic tetracycline (fluorocycline) Mechanism of Action
• Inhibits bacterial protein synthesis by binding to the 30S ribosome and preventing the incorporation of amino acids to the elongating peptide chain
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Eravacycline (Xerava®) Resistance
• Intrinsic multi-drug-resistant (MDR) efflux and ribosomal modification
• C7 and C9 substitution allows activity against some tetracycline-specific resistance mechanisms Efflux mediated by tet(A), tet(B), and tet(K) Ribosomal protection encoded by tet(M) and tet(Q)
• In vitro efficacy against Entreobacteriaceae ESBL producing AmpC producing
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Eravacycline (Xerava®)
Spectrum of Activity • Gram-positive bacteria Enterococcus faecalis Enterococcus faecium Staphylococcus aureus Streptococcus anginosus
• Gram-negative bacteria Citrobacter freundii Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Klebsiella oxytoca
• Anaerobic Bacteria Clostridium perfringens Bacteroides spp. Parabacteroides distasonis
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Eravacycline (Xerava®)
Dosing and Administration Dose • 1mg/kg every 12h over 60 minutes • Renal dose adjustment not required • Hepatic dose adjustment in patients with severe hepatic impairment (Child Pugh C) 1mg/kg q12h on day 1 1mg/kg q24h beginning on day 2
Duration • 4 to 14 days
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Eravacycline (Xerava®)
Warnings and Precautions
• Hypersensitivity reactions • Tooth discoloration and enamel hypoplasia • Inhibition of bone growth • Clostridioides difficile - Associated Diarrhea • Potential for microbial overgrowth • Development of drug-resistant bacteria
Adverse Reactions
• Infusion reactions (7.7%) • Nausea (6.5%) • Vomiting (3.7%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Eravacycline (Xerava®)
Drug interactions
• Strong CYP3A4 inducers Decrease exposure of eravacycline • Anticoagulants Eravacycline may depress plasma prothrombin activity Decrease dose of anticoagulant recommended
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Eravacycline (Xerava®)
Use in specific populations Pregnancy Avoid in 2nd and 3rd trimester Discoloration of teeth Inhibition of bone formation
Lactation Avoid during treatment and for 4 days after discontinuation No human data available
Geriatric Use No difference in safety and efficacy
Pediatric Use No safety or efficacy data available
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Eravacycline (Xerava®)
Clinical Trial Data Two comparator-controlled clinical trials in patients with cUTI, including pyelonephritis
• Study 1 Non-inferior to ertapenem Clinical cure (86.8% vs. 87.6%) • Study 2 Non-inferior to meropenem Clinical cure (90.8% vs. 91.2%)
Utility in clinical practice Marketed as an alternative to minimize carbapenem use
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Sarecycline (Seysara®)
Approved • August, 2018
Indications
• Non-nodular moderate to severe acne in patients 9 years of age and older
Limitations of use Efficacy beyond 12 weeks not established Safety beyond 12 months not established
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf. Sarecycline (Seysara®)
Class • Tetracycline (fluorocycline) Mechanism of Action • Mechanism for treating acne vulgaris is unknown
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf Sarecycline (Seysara®)
Dosing and Administration Dose • Dosing based on body weight 33-54 kg 60 mg 55-84 kg 100mg 85-136 kg 150 mg
Duration • 12 weeks, then reassess treatment
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf Sarecycline (Seysara®)
Warnings and Precautions
• Hypersensitivity reactions • Tooth discoloration and enamel hypoplasia • Inhibition of bone growth • Clostridioides difficile - Associated Diarrhea • Central Nervous System Effects • Intracranial Hypertension • Photosensitivity • Potential for microbial overgrowth • Development of drug-resistant bacteria
Adverse Reactions
• Nausea (3.1%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf Sarecycline (Seysara®)
Drug interactions
• P-gp Substrates Sarecycline may increase concentrations of P-gp substrates Dose reduction may be required • Anticoagulants Sarecycline may depress plasma prothrombin activity Decrease dose of anticoagulant recommended
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf Sarecycline (Seysara®)
Use in specific populations Pregnancy Avoid in 2nd and 3rd trimester Discoloration of teeth Inhibition of bone formation
Lactation Avoid use in breastfeeding women No human data available
Geriatric Use No safety or efficacy data available
Pediatric Use No safety or efficacy data available for patients < 9 years of age Safe and effective for patients ≥ 9 years
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf Sarecycline (Seysara®)
Clinical Trial Data • Study 1 Superior to placebo IGA success (21.9% vs. 10.5%) % reduction (52.2% vs. 35.2%) • Study 2 Superior to placebo IGA success (22.6% vs. 15.3%) % reduction (50.8% vs. 36.4%)
Utility in clinical practice Narrow spectrum tetracycline (Cutibacterium acnes strains) Reduces exposure to broad-spectrum antibiotics (doxycycline) Anti-inflammatory properties
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf
Omadacycline (Nuzyra®)
Approved • August, 2018
Indications
• Community-acquired bacterial pneumonia (CABP) • Acute bacterial skin and skin structure infections (ABSSSI)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf. Omadacycline (Nuzyra®) Class • Tetracycline (aminomethylcycline) Mechanism of Action
• Inhibits bacterial protein synthesis by binding to the 30S ribosome and blocks protein synthesis Resistance • Overcomes resistance by Tetracycline resistance active efflux pumps (tetK and tetL) Ribosomal protection proteins (tetM) • Active against Some S. aureus, S. pneumo and H. influenzae strains with macrolide resistance genes (erm A, erm B, ermC) Some strains with ciprofloxacin resistance genes (gyrA and parC) β-lactamase positive H. influenzae
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Omadacycline (Nuzyra®)
Spectrum of Activity - CABP
• Gram-positive bacteria Streptococcus pneumoniae Staphylococcus aureus (MSSA)
• Gram-negative bacteria Haemophilus influenzae Haemophilus parainfluenzae
• Other microorganisms Chlamydophila pneumoniae Legionella pneumophilia Mycoplasma pneumoniae
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf https://www.nuzyra.com/hcp/antimicrobial-activity Omadacycline (Nuzyra®)
Spectrum of Activity - ABSSSI
• Gram-positive bacteria Enterococcus faecalis Staphylococcus aureus (MSSA and MRSA) Staphylococcus lugdunensis Streptococcus anginosus grp Streptococcus intermedius Streptococcus constellatus Streptococcus pyogenes
• Gram-negative bacteria Enterobacter cloacae Klebsiella pneumoniae
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf https://www.nuzyra.com/hcp/antimicrobial-activity Omadacycline (Nuzyra®)
Dosing and Administration Dose • CABP Loading dose: 200mg IV over 60 minutes or 100mg IV over 30 minutes q12h x 2 doses Maintenance dose: 100mg IV over 30 minutes daily or 300mg PO daily • ABSSSI Loading dose: 200mg IV over 60 minutes or 100mg IV over 30 minutes q12h x 2 doses Maintenance dose: 100mg IV over 30 minutes daily or 300mg PO daily Or Loading dose 450mg PO q24h x 2 doses 300mg PO daily
• Renal and hepatic dose adjustment not required
Duration • 7 to 14 days
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Omadacycline (Nuzyra®) Warnings and Precautions • CABP - Increase risk of mortality compared to moxifloxacin (2% vs. 1%) Cause not established • Tooth discoloration and enamel hypoplasia • Inhibition of bone growth • Hypersensitivity reactions • Clostridioides difficile - Associated Diarrhea • Intracranial Hypertension • Photosensitivity • Development of drug-resistant bacteria
Adverse Reactions • Nausea (21.9%) • Vomiting (11.4%) • Infusion site reactions (4.1%) • LFT elevation (3.7% - 4.1%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Omadacycline (Nuzyra®)
Drug interactions
• Anticoagulants Omadacycline may depress plasma prothrombin activity Decrease dose of anticoagulant recommended • Antacids and Iron containing products Absorption is impaired by aluminum, calcium, magnesium, iron
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Omadacycline (Nuzyra®)
Use in specific populations Pregnancy Avoid in 2nd and 3rd trimester Discoloration of teeth Inhibition of bone formation Limited data available
Lactation Avoid during treatment and for 4 days after discontinuation No human data available
Geriatric Use Insufficient data Lower clinical success rates in patients ≥ 65 years
Pediatric Use No safety or efficacy data available
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Omadacycline (Nuzyra®)
Clinical Trial Data - ABSSSI Trial 1 IV for 3 days, with the option to transition to PO (omadacycline vs. linezolid) Non-inferior to linezolid Clinical success at early clinical response (84.8% vs. 85.5%) Clinical response at post-therapy evaluation (87.3% vs. 82.2%)
Trial 2 PO omadacycline vs. PO linezolid Non-inferior to linezolid Clinical success at early clinical response (84.8% vs. 85.5%) Clinical response at post-therapy evaluation (87.3% vs. 82.2%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf Omadacycline (Nuzyra®)
Clinical Trial Data - CABP IV for 3 days, with the option to transition to PO (omadacycline vs. moxifloxacin) Non-inferior to moxifloxacin Clinical success at early clinical response (81.1% vs. 82.7%) Clinical response at post-therapy evaluation (87.6% vs. 85.1%)
Utility in clinical practice Treats CAP caused by resistant S. pneumoniae Broad spectrum - empiric monotherapy for ABSSSI
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf
Rifamycin (Aemcolo®)
Approved • November, 2018 Indications • Traveler’s diarrhea caused by noninvasive strains of E. coli in adults Limitations of use • Not for use in patients with diarrhea complicated by fever or bloody stool • Indicated for E. coli only
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf. Rifamycin (Aemcolo®)
Class • Ansamycin Mechanism of Action
• Blocks DNA transcription by inhibiting DNA-dependent RNA polymerase Resistance • Point mutations in the RNA polymerase beta subunit associated withresistance
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf Rifamycin (Aemcolo®)
Dosing and Administration Dose 388mg (2 tablets) PO BID for 3 days
• Safety and efficacy in renal and hepatic impairment not studied
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf Rifamycin (Aemcolo®) Warnings and Precautions • Risk of persistent or worsening diarrhea complicated by fever and/or bloody stool • Clostridioides difficile - Associated Diarrhea • Development of drug-resistant bacteria
Adverse Reactions • Constipation (3.5%) • Headache (3.3%)
Drug interactions • None studied
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf Rifamycin (Aemcolo®)
Use in specific populations Pregnancy No human data available No evidence of fetal harm in animal studies
Lactation No human data available
Geriatric Use Insufficient data Minimal absorption, minimal difference in safety/efficacy expected
Pediatric Use No safety or efficacy data available
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf Rifamycin (Aemcolo®)
Clinical Trial Data Rifamycin 388mg PO BID for 3 days Time to last unformed stool Superior to placebo (46h vs. 68h) Clinical cure Superior to placebo (80.4% vs. 56.9%)
Utility in clinical practice Alternative to fluoroquinolones for Traveler’s diarrhea
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf
Imipenem, cilastatin, relebactam (Recabrio®)
Approved
• July, 2019
Indications
• Complicated urinary tract infections (cUTI) • Complicated intra-abdominal infections (cIAI) • Hospital-acquired bacterial pneumonia (HABP) • Ventilator-acquired bacterial pneumonia (VABP)
*Reserved for patients ≥ 18 years of age with limited or no alternative treatment options
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086080/#:~:text=This%20review%20focuses%20on%20the,2019)%20are%20new%20therapeutic%20options. Imipenem, cilastatin, relebactam (Recabrio®)
Class
• Carbapenem/β-lactamase inhibitor Mechanism of Action
• Inhibits bacterial cell wall synthesis (Imipenem)
• β-lactamase inhibitor (relebactam) Protects imipenem from degradation by β-lactamases SVH, TEM, CTX-M, Enterobacter cloacae P99, PDC, KPC
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212819s000lbl.pdf Imipenem, cilastatin, relebactam (Recabrio®) Resistance
• No cross-resistance with other classes of antibacterial drugs Some isolates resistant to cephalosporins and carbapenems are susceptible to imipenem/cilastatin/relebactam
• β-lactam resistance mechanisms in gram-negative organisms: β-lactamase production Up-regulation of efflux pumps Loss of outer membrane porins
• Resistant to most isolates containing metalo-beta-lactamases and oxacillinases with carbapenemase activity
• Resistant Enterobacteriaceae MBL or oxacillinase producing
• Resistant Pseudomonas aeruginosa MBL, KPC, PER, GES, VEB, PDC producing
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212819s000lbl.pdf Imipenem, cilastatin, relebactam (Recabrio®)
Spectrum of Activity
• Aerobic gram-negative bacteria Acinetobacter baumannii complex Enterobacter cloacae complex Escherichia coli Haemophilus influenzae Klebsiella spp. Pseudomonas aeruginosa Serratia marcescens
• Anaerobic Bacteria Bacteroides spp. Fusobacterium nucleatum Parabacteroides distasonis
https://www.merckconnect.com/recarbrio/mechanism-of-action/?#AntimicrobialActivity Imipenem, cilastatin, relebactam (Recabrio®)
Dosing and Administration Dose • 1.25g IV q6h over 3 hours Imipenem 500mg, cilastatin 500mg, relebactam 250mg Renal dose adjustment required CrCl < 60 mL/min
Duration • 4 to 14 days
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212819s000lbl.pdf https://www.merckconnect.com/recarbrio/dosing-administration/ Imipenem, cilastatin, relebactam (Recabrio®)
Pharmacokinetics Elimination • Half-life of ~1hr
Metabolism • Cilastatin inhibits metabolism of imipenem by dehydropeptidase in the kidneys • Relebactam is minimally metabolized
Excretion • Renal
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Imipenem, cilastatin, relebactam (Recabrio®)
Warnings and Precautions
• Hypersensitivity reactions • Seizures and CNS reactions • Increased seizure potential with Valproic Acid • Clostridioides difficile–associated diarrhea (CDAD)
Adverse Reactions
• Diarrhea (6%) • Nausea (6%) • Headache (4%) • Vomiting (3%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Imipenem, cilastatin, relebactam (Recabrio®)
Use in specific populations Pregnancy Embryonic loss observed in monkeys treated with imipenem/cilastatin Fetal abnormalities in mice treated with relebactam Insufficient human data
Lactation Insufficient data in humans Relebactam present in milk of lactating rats
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212819s000lbl.pdf Imipenem, cilastatin, relebactam (Recabrio®)
Use in specific populations Geriatric Use No difference in safety and efficacy 31% of patients in clinical trials were ≥ 65 years 11.6 % of patients in clinical trials were ≥ 75 years
Pediatric Use No data
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Imipenem, cilastatin, relebactam (Recabrio®)
Clinical Trial Data – HABP/VABP Trial 1 Imipenem/cilastatin/relebactam vs. Piperacillin/Tazobactam Non-inferior to Piperacillin/Tazobacctam All cause mortality at 28 days (15.9% vs. 21.3%) Higher mortality in HABP alone (12.7% vs. 11.5%) Lower mortality with VABP and ventilated HABP (19.7% vs. 30.9%)
Trial 2 Imipenem/cilastatin/relebactam vs. imipenem/cilastatin + colistin Non-inferior All-cause mortality (9.5% vs 30%) Clinical response at day 28 (71.4% vs. 40%) Small sample size (n=30)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Imipenem, cilastatin, relebactam (Recabrio®)
Clinical Trial Data – cUTI and cIAI Two individual trials Imipenem/cilastatin + placebo vs Imipenem/cilastatin/relebactam Designed to identify side effects Increased diarrhea, LFT elevation with Imipenem/cilastatin/relebactam
Utility in clinical practice Reserved for MDR organisms
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Cefiderocol (Fetroja®)
Approved
• November 11, 2019
Indications
• Complicated urinary tract infections (cUTI) Reserved for use in patients ≥ 18 years of age with limited treatment options • Hospital-acquired bacterial pneumonia • Ventilator-associated bacterial pneumonia
https://www.fetroja.com/mechanism-of-action/ Cefiderocol (Fetroja®)
Class
• Siderophore cephalosporin
Mechanism of Action
• Inhibits bacterial cell wall synthesis
• Functions as a siderophore to gain access via the bacteria’s iron-transport system Binds to extracellular free ferric iron Evades resistance by overcoming porin channel alterations
https://www.fetroja.com/mechanism-of-action/ Cefiderocol (Fetroja®) Structure
https://www.fetroja.com/overcoming-carbapenem-resistance Cefiderocol (Fetroja®)
Mechanism of Action
https://www.fetroja.com/mechanism-of-action/ Cefiderocol (Fetroja®) Resistance
• No cross-resistance with other classes of antibacterial drugs
• Stable against all classes of β-lactamases
• Overcomes efflux pump up-regulation
https://www.fetroja.com/mechanism-of-action/ Cefiderocol (Fetroja®) Resistance
https://www.fetroja.com/mechanism-of-action/ Cefiderocol (Fetroja®)
Spectrum of Activity
• Aerobic gram-negative bacilli Acinetobacter baumannii complex Escherichia coli Enterobacter cloacae complex Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Serratia marcescens
In vitro activity Citrobacter freundii complex, Citrobacter koseri, Klebsiella aerogenes, Klebsiella oxytoca, Morganella morganii, Proetus vulgaris, Providencia rettgeri, Stenotrophomonas maltophilia
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Cefiderocol (Fetroja®)
Dosing and Administration Dose • 2g IV q8h over 3 hours Renal dose adjustment required CrCl < 60 mL/min CrCl ≥ 120 mL/min
Duration • 7 to 14 days
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Cefiderocol (Fetroja®)
Pharmacokinetics Elimination • Half-life of 2-3 hours • Clearance ~ 5L/hr
Metabolism • Minimal metabolism
Excretion • Renal
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Cefiderocol (Fetroja®)
Warnings and Precautions
• Increase in all-cause mortality in patients with carbapenem-resistant gram-negative infections • Hypersensitivity reactions • Clostridioides difficile–associated diarrhea (CDAD) • Seizures and other CNS reactions • Development of Drug-Resistant bacteria
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Cefiderocol (Fetroja®) Adverse Reactions • Diarrhea (4%) • Infusion site reactions (4%) • Constipation (3%) • Rash (3%)
Drug/Laboratory Test Interactions • False-positive dipstick tests Urine protein, ketones, occult blood
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Cefiderocol (Fetroja®)
Use in specific populations Pregnancy No data available Cephalosporins typically safe for use in pregnancy
Lactation No data in humans Detected in milk of lactating rats (6% of peak plasma level)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Cefiderocol (Fetroja®)
Use in specific populations Geriatric Use No difference in safety and efficacy
Pediatric Use No data
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub
Lefamulin (Xenleta®)
Approved
• August, 2019
Indications
• Community Acquired Bacterial Pneumonia
Future Indications
• Acute Bacterial SSTI Phase 2 trials complete • Complicated UTI Phase 1 trials initiated
Novel Antibiotics | Lefamulin | Nabriva.com. Lefamulin (Xenleta®)
Class Pleuromutilin antibacterial agent Mechanism of Action Inhibits bacterial protein synthesis through interaction with the A- and P- sites of the peptidyl transferase of the 23S rRNA of the 50S subunit Interacts via hydrogen bonds, hydrophobic interactions, and Van der Waals forces
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212819s000lbl.pdf Lefamulin (Xenleta®) Resistance
• Modifications of the ribosomal target ABC-F proteins Vga (A,B,E), Isa(E), sal (A), Cfr methyl transferase Cfr methyltransferase can mediate cross-resistance between lefamulin and lincosamides, oxazolidinones, and streptogramins • Mutation of ribosomal proteins L3 and L4
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf Lefamulin (Xenleta®)
Spectrum of Activity Gram-positive Bacteria Streptococcus pneumoniae Staphylococcus aureus (MSSA)
Gram-negative Bacteria Haemophilus influenzae
Other Bacteria Mycoplasma pneumoniae Chlamydophila pneumoniae Legionella pneumophilia
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf Lefamulin (Xenleta®)
Potential Spectrum of Activity Gram-positive Bacteria Staphylococcus aureus (MRSA) Streptococcus agalactiae Streptococcus anginosus Streptococcus mitis Streptococcus pyogenes Streptococcus salivarius
Gram-negative Bacteria Haemophilus parainfluenzae Moraxella catarrhalis
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf Lefamulin (Xenleta®)
Dosing and Administration Dose • 150mg IV q12h over 60 minutes • 600mg PO q12h Administer 1 hours before or 2 hours after meals
Duration • 5-7 days
Dose adjustment
• Hepatic Impairment 150mg IV q24h over 60 minutes (Child-Pugh Class C) Tablets not recommended with moderate or severe hepatic impairment (Child-Pugh Class B or C)
• Renal dose adjustment not required
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf Lefamulin (Xenleta®) Pharmacokinetics Absorption Decreased bioavailability when administered with food (PO)
Metabolism CYP3A4 metabolism
Elimination Elimination half-life ~ 8 hours
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf Lefamulin (Xenleta®)
Warnings and Precautions
• QT Prolongation • Embryo-Fetal Toxicity Verify pregnancy status before initiation • Clostridioides difficile-associated diarrhea (CDAD) • Development of drug resistant bacteria
Adverse Reactions
• Diarrhea (12%) • Infusion site reaction (7%) • Nausea (5%)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Lefamulin (Xenleta®)
Drug Interactions Strong CYP3A4 inducers/inhibitors Strong P-gp inducers/inhibitors
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pub Lefamulin (Xenleta®)
Use in specific populations Pregnancy May cause fetal harm Pregnancy pharmacovigilance program established for Xenleta
Lactation No human data Concentrated in mild of lactating rats Recommend pumping and discarding milk during administration and for 2 days after discontinuation of lefamulin
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf Lefamulin (Xenleta®)
Use in specific populations Geriatric Use No difference in safety and efficacy 41.5% of patients in clinical trials were ≥ 65 years
Pediatric Use Safety and efficacy not established
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf Lefamulin (Xenleta®)
Clinical Trial Data Two multicenter, multinational, double-blind, double-dummy, non-inferiority trials • Trial 1 Lefamulin (5-10 days) compared to Moxifloxacin ± Linezolid (7-10 days) IV administration of all antibiotics for at least 3 days before transition to PO Non-inferior to Moxifloxacin ± Linezolid Early Clinical Response 87.3% vs. 90.2% Clinical Response at Test of Cure 80.8% vs. 83.6% • Trial 2 PO Lefamulin (5 days) compared to PO Moxifloxacin (7 days) Non-inferior to Moxifloxacin ± Linezolid Early Clinical Response 90.2% vs. 90.2% Clinical Response at Test of Cure 87.0% vs. 89.1%
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf
Pretomanid
Approval • August, 2019 Indications • Mycobacterium tuberculosis Approved only in combination with bedaquiline and linezolid in drug-resistant tuberculosis Class Nitroimidazooxazine antimycobacterial drug Mechanism of Action Blocks mycobacterial cell wall production by inhibiting mycolic acid biosynthesis
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf Pretomanid Resistance
• Mutations in M. tuberculosis genes ddn, fgd l, fbiA, fbiB, fbiC Products of these genes are involved in bioreductive activation of pretomanid • Other resistance mechanism? Not all resistant isolates have mutations in the identified M. tuberculosis genes
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf Pretomanid
Dosing and Administration Dose • Pretomanid 200mg tablet daily Administer with Linezolid 1200mg daily x 26 weeks Bedaquiline 400mg PO x 2 weeks, then 200mg 3x/week for 24 weeks Duration may be extended beyond 6 weeks
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf Pretomanid Warnings and Precautions
• Hepatotoxicity Discontinue if: ALT/AST + bilirubin > 2 x ULN ALT/AST > 8 x ULN ALT/AST > 5 x ULN for longer than 2 weeks • Myelosuppression Monitor blood counts Known adverse reaction to linezolid • Peripheral and optic neuropathy Neuropathy associated with linezolid • Lactic Acidosis Associated with linezolid • QT Prolongation Associated with bedaquiline use Drug Interactions Strong CYP3A4 inducers Avoid co-administration
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf Pretomanid
Use in specific populations Pregnancy Insufficient data No associated embryofetal effects a 2 times the AUC in humans
Lactation No human data Detected in milk of lactating rats
Geriatric Use Insufficient data
Pediatric Use Safety and efficacy not established
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf Pretomanid
Clinical Trial Data
• Open-label study in three centers N = 109, 51% HIV-positive Pretomanid + bedaquiline + linezolid for 6 months Extended to 9 months in 2 patients 89% culture negative 6-months after treatment
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf Antibiotics in Development Antibiotics in Development Overview 40 antibiotics currently in development 13 in Phase 3 12 in Phase 2 15 in Phase 1
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2020/04/tracking-the-global-pipeline-of-antibiotics-in-development Antibiotics in Development Overview
Target Organisms
• Gram-negative ESKAPE Pathogens Enterococcus faecium Staphylococcus aureus Klebsiella pneumoniae Acinetobacter baumannii Pseudomonas aeruginosa Enterobacter Spp.
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2020/04/tracking-the-global-pipeline-of-antibiotics-in-development Antibiotics in Development Overview
Target Organisms
WHO Critical Threat Pathogens Acinetobacter baumannii – Carbapenem resistant (CRAB) Pseudomonas aeruginosa – Carbapenem resistant (CRPA) Enterobacteriaceae – Carbapenem resistant, ESBL-producing
CDC Urgent threat pathogens Acinetobacter baumannii – Carbapenem resistant (CRAB) Candida auris Clostridioides difficile Enterobacteriaceae – Carbapenem resistant Neisseria gonorrheae – Drug resistant
https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed Antibiotics in Development Overview History 1 in 5 infectious disease drugs that reach human trials are approved
Current landscape 11 antibiotics in development have a novel mechanism of action or drug class 35 companies with antibiotics in clinical development 1 ranks in the top 50 pharmaceutical companies by sales 75% are pre-revenue Too few antibiotics in development to meet anticipated need
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2020/04/tracking-the-global-pipeline-of-antibiotics-in-development Antibiotics in Development
• Phase 3 Cefepime + enmetazobactam • Sulopenem & sulopenem-etzadroxil- Cefepime + taniborbactam probenecid Cefilavancin • Solithromycin Ceftobiprole • Tebipenem & tebipenem pivoxil Contezolid & contezolid acefosamil hydrobromide Cespotidacin • Zolidflodacin Iclaprim Ridinilazole Sulbactam + durlobactam Antibiotics in Development Cefepime + enmetazobactam Current Status Phase 3 Class Benzoquinolozine fluoroquinolone Mechanism of Action Targets DNA gyrase preferentially over topoisomerase IV Indication SSTI Hospital Acquired Bacterial Pneumoniae Target organisms ESKAPE pathogens S. aureus, including MRSA Does not cover CDC urgent or WHO critical threat pathogens
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Cefepime + enmetazobactam
Current Status Phase 3
Class β-lactam (cephalosporin) + β- lactamase inhibitor
Mechanism of Action Targets Penicillin Binding Protein (PBP) and β-lactamase
Indication Complicated intra-abdominal infections Complicated UTI (including pyelonephritis) Hospital Acquired Bacterial Pneumonia Ventilator Associated Bacterial Pneumonia
Target organisms ESKAPE Pathogens K. pneumoniae, P. aeruginosa, Enterobacter Possibly S. aureus CDC urgent or WHO critical threat pathogens ESBL producing organisms, possibly CRE
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Cefepime + taniborbactam Current Status Phase 3 Class β-lactam (cephalosporin) + β- lactamase inhibitor (cyclic boronate) Mechanism of Action Inhibits cell wall synthesis - targets Penicillin Binding Protein (PBP) Inhibits β-lactamase Indication Complicated UTI (excluding pyelonephritis) Target organisms ESKAPE pahtogens K. pneumoniae, P. aeruginosa, Enterobacter spp. Possibly S. aureus CDC urgent or WHO critical pathogens CRE, possibly CRPA https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Cefilavancin Current Status Phase 3 Class Glycopeptide-β-lactam hybrid Mechanism of Action Inhibits cell wall synthesis - targets Penicillin Binding Protein (PBP) Inhibits peptidoglycan chain elongation Indication Complicated UTI (excluding pyelonephritis) Target organisms ESKAPE pathogens S. aureus (MRSA) Does not cover CDC urgent or WHO critical pathogens
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Ceftobiprole Current Status Phase 3
Class β-lactam (cephalosporin)
Mechanism of Action Inhibits cell wall synthesis - targets Penicillin Binding Protein (PBP)
Indication SSTI Community Acquired Bacterial Pneumonia Hospital Acquired Bacterial Pneumonia S. aureus bacteremia
Target organisms ESKAPE pathogens S. aureus (MRSA), K. pneumoniae, Enterobacter spp. Does not cover CDC urgent or WHO critical pathogens
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Contezolid & contezolid acefosamil Current Status Phase 3 Class Oxazolidinone Mechanism of Action Inhibits protein synthesis Targets bacterial 50S ribosomal subunit Indication SSTI Target organisms ESKAPE pathogens E. faecium, S. aureus (MRSA) Does not cover CDC urgent or WHO critical pathogens
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Gespotidacin Current Status Phase 3
Class Triazaacenaphthylene
Mechanism of Action Inhibits DNA synthesis Targets bacterial topoisomerase II at a novel A subunit site
Indication Uncomplicated UTI Uncomplicated urogenital gonorrhea
Target organisms ESKAPE pathogens S. aureus (MRSA) CDC urgent or WHO critical pathogens Drug-resistant N. gonorrhoeae Possibly ESBP https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Iclaprim
Current Status Phase 3
Class 2,4 diaminopyrimidine
Mechanism of Action Dihydrofolate reductase inhibitor
Indication Clostridioides difficile infection
Target organisms Does not cover ESKAPE pathogens CDC urgent or WHO critical pathogens C. difficile https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Ridinilazole Current Status Phase 3 Class Bis-benzimidazole Mechanism of Action Inhibits cell division Reduces toxin production Indication Clostridioides difficile infection Target organisms Does not cover ESKAPE pathogens CDC urgent or WHO critical pathogens C. difficile https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Sulbactam + durlobactam
Current Status Phase 3
Class β-lactam + β-lactamase inhibitor
Mechanism of Action Inhibits cell wall synthesis by targeting Penicillin Binding Protein (PBP) β-lactamase inhibitor
Indication Bacteremia Complicated UTI (including pyelonephritis) Hospital Acquired Bacterial Pneumoniae Ventilator Associated Bacterial Pneumoniae
Target organisms ESKAPE pathogens A. baumannii CDC urgent or WHO critical pathogens CRAB
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Sulopenem & sulopenem-etzadroxil-probenecid Current Status Phase 3 Class β-lactam (carbapenem) Mechanism of Action Inhibits cell wall synthesis by targeting Penicillin Binding Protein (PBP) Indication Prostatitis Community Acquired Bacterial Pneumonia Complicated intra-abdominal infections Complicated UTI Gonococcal urethritis Pelvic inflammatory disease Uncomplicated UTI https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Sulopenem & sulopenem-etzadroxil-probenecid
Target organisms ESKAPE pathogens K. pneumoniae, Enterobacter spp. CDC urgent or WHO critical pathogens ESBL producing organisms Drug-resistant N. gonorrhoeae
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Solithromycin Current Status Phase 3 Class Macrolide Mechanism of Action Inhibits bacterial protein synthesis Targets the bacterial 50S ribosomal subunit Indication Community Acquired Bacterial Pneumonia Uncomplicated urogenital gonorrhea Target organisms Does not cover ESKAPE pathogens CDC urgent or WHO critical pathogens Drug-resistant N. gonorrhoeae
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Tebipenem & tebipenem pivoxil hydrobromide
Current Status Phase 3 Approved for use in Japan (Orapenem®) for pneumonia, otitis media, sinusitis
Class Carbapenem
Mechanism of Action Inhibits cell wall synthesis by targeting Penicillin Binding Protein (PBP)
Indication Complicated UTI (including pyelonephritis) Community Acquired Bacterial Pneumonia Diabetic foot infection
Target organisms ESKAPE pathogens K. pneumoniae Possibly A. baumannii, P. aeruginosa CDC urgent or WHO critical pathogens ESBL producing organisms
https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Antibiotics in Development Zoliflodacin Current Status Phase 3 Class Spiropyrimidinetrione
Mechanism of Action Inhibits bacterial DNA synthesis Targets bacterial type II topoisomerase
Indication Uncomplicated gonorrhea Target organisms ESKAPE pathogens S. aureus CDC urgent or WHO critical pathogens Drug-resistant N. gonorrhoeae https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development Questions? Assessment Questions
1. Which of the following statements regarding new antibacterial agents is true? A. Most are FDA approved to treat a broad range of infections B. Recently approved antibiotics are likely to become first-line agents C. Many have a novel mechanism of action D. Most are reserved for infections caused by organisms that are resistant to existing antibiotics
2. The majority of antibiotics currently in development target which pathogen(s)? A. Gram-positive organisms B. Gram-negative ESKAPE pathogens C. Drug-resistant Neisseria gonorrheae D. Drug-resistant Clostridioides difficile References
1. Aemcolo [package insert]. San Diego, Ca: Aries Pharmaceuticals, Inc; 2018.
2. Antibiotics Currently in Global Clinical development. Data Visualization April 15, 2020. PEW website. Available at: Antibiotics Currently in Clinical Development | The Pew Charitable Trusts (pewtrusts.org). Accessed February 28, 2021.
3. Clinical study of S-649266 for the treatment of nosocomial pneumonia caused by gram-negative pathogens (APEKS-NP). Available at: https://clinicaltrials.gov/ct2/show/NCT03032380. Accessed Jan. 20, 2020.
4. Fetroja [package insert]. Florham Park, NJ: Shionogi Inc; 2019.
5. Food and Drug Administration. FDA Antibacterial Susceptibility Test Interpretive Criteria. Cefiderocol injection. https://www.fda.gov/drugs/development-resources/cefiderocol-injection. Accessed Feb. 10, 2020.
6. Hagwat SS, et al. Levonadifloxacin, a novel broad-spectrum Anti-MRSA benzoquinolizine quinolone agent: review of current evidence. Drug Des Devel Ther 2019, 13: 4351-4365.
7. Ito A, Sato T, Ota M, et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against gram-negative bacteria. Antimicrob Agents Chemother 2017;62:e01454-17.
8. Ito A, Nishikawa T, Matsumoto S, et al. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother 2016;60:7396-7401.
9. Katsube T, Echols R, Wajima T. Pharmacokinetic and pharmacodynamic profiles of cefiderocol, a novel siderophore cephalosporin. Clin Infect Dis 2019;69(Suppl7):S552-S558. References
10. Mulani S, Kamble EE, Kumkar SN, Tawre SM, Pardesi KR. Emerging Strategies to Combat ESKAPE Pathogens in the Era of Antimicrobial Resistance: A Review. Front Microbiol 2019;10:539.
11. Nuzyra [package insert]. Boston, MA: Paratek pharmaceuticals, Inc; 2018.
12. Nuzyra website. Available at:https://www.nuzyra.com/hcp/. Accessed February 26, 2021.
13. Pretomanid [package insert]. South San Francisco, CA: Achaogen, Inc; 2018.
14. Seysara [package insert]. Madison, NJ: Allergan USA, Inc; 2018.
15. Moore AY, Charles JE, Moore S. Sarecycline: a narrow spectrum tetracycline for the treatment of moderate- to-severe acne vulgaris. Future Microbiology 2019;14;4. Available at: https://www.futuremedicine.com/doi/10.2217/fmb-2019-0199. Accessed February 28, 2021.
16. Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: A phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2018;18: 1319-1328.
17. Sato T, Yamawaki K. Cefiderocol: Discovery, chemistry, and in vivo profiles of a novel siderophore cephalosporin. Clin Infect Dis 2019;69(Suppl 7):S538-S543.
18. Tracking the Global Pipeline of Antibiotics in Development, April 2020. PEW website. Available at: https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2020/04/tracking-the-global-pipeline-of- antibiotics-in-development. Accessed February 28, 2020. References
18. WHO publishes list of bacteria for which new antibiotics are urgently needed. 2017. World Health Organization website. Available at: https://www.who.int/news/item/27-02-2017-who-publishes-list-of- bacteria-for-which-new-antibiotics-are-urgently-needed. Accessed February 10, 2021.
19. Yamano Y. In vitro activity of cefiderocol against a broad range of clinically important gram-negative bacteria. Clin Infect Dis 2019;69(Suppl7):S544-S551.
20. Xenleta [package insert]. Nabriva Therapeutics US; 2019.
21. Xerava [package insert]. Watertown, MA: Tetraphase Pharmaceuticals, Inc; 2018.
22. Xerava™ website. Available at: https://www.xerava.com/. Accessed February 26, 2021.
23. Zemdri [package insert]. South San Francisco, CA: Achaogen, Inc; 2018.
24. Zemdri website. Available at: https://zemdri.com/. Accessed February 26, 2021.