antibiotics an update on recently approved and

Antibiotics – an update on recently approved and investigational drugsJenner 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 Questions1. 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


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


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



Dosing and Administration

Dose

• 15mg/kg q24h over 30 minutes

• Renal dose adjustment required

Duration

• 4 to 7 days



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



Adverse Reactions

• Decreased renal function (11%)

• Diarrhea (7%)

• Hypertension (7%)

• Nausea/Vomiting (4%)



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



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)


https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf.


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

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




• Gram-positive bacteria Enterococcus faecalis

Enterococcus faecium

Staphylococcus aureus

Streptococcus anginosus

• Gram-negative bacteria Citrobacter freundii

Enterobacter cloacae

Escherichia coli


Klebsiella oxytoca

• Anaerobic Bacteria Clostridium perfringens

Bacteroides spp.

Parabacteroides distasonis




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





• 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%)



Drug interactions

• Strong CYP3A4 inducers

Decrease exposure of eravacycline

• Anticoagulants

Eravacycline may depress plasma prothrombin activity

Decrease dose of anticoagulant recommended




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



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%)


Marketed as an alternative to minimize carbapenem use





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.


Class• Tetracycline (fluorocycline)

Mechanism of Action• Mechanism for treating acne vulgaris is unknown

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209521s000lbl.pdf


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








• Central Nervous System Effects

• Intracranial Hypertension

• Photosensitivity

• Potential for microbial overgrowth


Adverse Reactions

• Nausea (3.1%)



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








Lactation Avoid use in breastfeeding women


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



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%)


Narrow spectrum tetracycline (Cutibacterium acnes strains)

Reduces exposure to broad-spectrum antibiotics (doxycycline)

Anti-inflammatory properties





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.


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


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.nuzyra.com/hcp/antimicrobial-activity


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



https://www.nuzyra.com/hcp/antimicrobial-activity



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 dailyOr

Loading dose 450mg PO q24h x 2 doses

300mg PO daily

• Renal and hepatic dose adjustment not required

Duration

• 7 to 14 days




• CABP - Increase risk of mortality compared to moxifloxacin (2% vs. 1%) Cause not established





• Intracranial Hypertension

• Photosensitivity


Adverse Reactions

• Nausea (21.9%)

• Vomiting (11.4%)

• Infusion site reactions (4.1%)

• LFT elevation (3.7% - 4.1%)



Drug interactions

• Anticoagulants

Omadacycline may depress plasma prothrombin activity


• Antacids and Iron containing products

Absorption is impaired by aluminum, calcium, magnesium, iron







Limited data available

Lactation Avoid during treatment and for 4 days after discontinuation


Geriatric Use Insufficient data

Lower clinical success rates in patients ≥ 65 years

Pediatric Use No safety or efficacy data available



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 Trial Data - CABP

IV for 3 days, with the option to transition to PO (omadacycline vs. moxifloxacin)

Non-inferior to moxifloxacin




Treats CAP caused by resistant S. pneumoniae

Broad spectrum - empiric monotherapy for ABSSSI




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.


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



Dose

388mg (2 tablets) PO BID for 3 days

• Safety and efficacy in renal and hepatic impairment not studied



Warnings and Precautions• Risk of persistent or worsening diarrhea complicated by fever and/or bloody stool



Adverse Reactions• Constipation (3.5%)

• Headache (3.3%)

Drug interactions• None studied




Pregnancy


No evidence of fetal harm in animal studies

Lactation


Geriatric Use

Insufficient data

Minimal absorption, minimal difference in safety/efficacy expected

Pediatric Use

No safety or efficacy data available



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



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)


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086080/#:~:text=This%20review%20focuses%20on%20the,2019)%20are%20new%20therapeutic%20options.


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


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




• Aerobic gram-negative bacteria

Acinetobacter baumannii complex

Enterobacter cloacae complex

Escherichia coli


Klebsiella spp.

Pseudomonas aeruginosa

Serratia marcescens

• Anaerobic Bacteria

Bacteroides spp.

Fusobacterium nucleatum

Parabacteroides distasonis

https://www.merckconnect.com/recarbrio/mechanism-of-action/?#AntimicrobialActivity



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.merckconnect.com/recarbrio/dosing-administration/


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




• 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%)




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




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



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)



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


Reserved for MDR organisms




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/


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


Cefiderocol (Fetroja®)Structure

https://www.fetroja.com/overcoming-carbapenem-resistance

Cefiderocol (Fetroja®)Mechanism of Action



Resistance• No cross-resistance with other classes of antibacterial drugs

• Stable against all classes of β-lactamases

• Overcomes efflux pump up-regulation


Cefiderocol (Fetroja®)Resistance




• Aerobic gram-negative bacilli

Acinetobacter baumannii complex

Escherichia coli

Enterobacter cloacae complex


Proteus mirabilis


Serratia marcescens

In vitro activity

Citrobacter freundii complex, Citrobacter koseri, Klebsiella aerogenes, Klebsiella oxytoca, Morganella morganii, Proetus vulgaris, Providencia rettgeri, Stenotrophomonas maltophilia




Dose

• 2g IV q8h over 3 hours

Renal dose adjustment required

CrCl < 60 mL/min

CrCl ≥ 120 mL/min

Duration

• 7 to 14 days



Pharmacokinetics

Elimination

• Half-life of 2-3 hours

• Clearance ~ 5L/hr

Metabolism

• Minimal metabolism

Excretion

• Renal




• Increase in all-cause mortality in patients with carbapenem-resistant gram-negative infections


• Clostridioides difficile–associated diarrhea (CDAD)

• Seizures and other CNS reactions

• Development of Drug-Resistant bacteria


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




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)




Geriatric Use


Pediatric Use

No data



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.

https://www.nabriva.com/pipeline-research


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


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




Gram-positive Bacteria

Streptococcus pneumoniae

Staphylococcus aureus (MSSA)

Gram-negative Bacteria


Other Bacteria

Mycoplasma pneumoniae

Chlamydophila pneumoniae

Legionella pneumophilia



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




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



Pharmacokinetics

Absorption Decreased bioavailability when administered with food (PO)

Metabolism CYP3A4 metabolism

Elimination Elimination half-life ~ 8 hours




• 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%)



Drug Interactions

Strong CYP3A4 inducers/inhibitors

Strong P-gp inducers/inhibitors




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




Geriatric Use


41.5% of patients in clinical trials were ≥ 65 years

Pediatric Use

Safety and efficacy not established



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%



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

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


Pretomanid


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


Pretomanid


• 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


Pretomanid


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


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


Pretomanid

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


Overview

Target Organisms

• Gram-negative ESKAPE Pathogens

Enterococcus faecium

Staphylococcus aureus


Acinetobacter baumannii


Enterobacter Spp.




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


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




• Phase 3

Cefepime + enmetazobactam

Cefepime + taniborbactam

Cefilavancin

Ceftobiprole

Contezolid & contezolid acefosamil

Cespotidacin

Iclaprim

Ridinilazole

Sulbactam + durlobactam

• Sulopenem & sulopenem-etzadroxil-probenecid

• Solithromycin

• Tebipenem & tebipenem pivoxilhydrobromide

• Zolidflodacin

Antibiotics in DevelopmentCefepime + 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


Antibiotics in DevelopmentCefepime + 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


Antibiotics in DevelopmentCefepime + 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


Antibiotics in DevelopmentCefilavancin

Current Status

Phase 3

Class

Glycopeptide-β-lactam hybrid

Mechanism of Action


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


Antibiotics in DevelopmentCeftobiprole

Current Status

Phase 3

Class

β-lactam (cephalosporin)

Mechanism of Action


Indication

SSTI

Community Acquired Bacterial Pneumonia

Hospital Acquired Bacterial Pneumonia

S. aureus bacteremia

Target organisms

ESKAPE pathogens

S. aureus (MRSA), K. pneumoniae, Enterobacter spp.



Antibiotics in DevelopmentContezolid & 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)



Antibiotics in DevelopmentGespotidacin

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)


Drug-resistant N. gonorrhoeae

Possibly ESBP



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


C. difficile



Ridinilazole

Current Status

Phase 3

Class

Bis-benzimidazole

Mechanism of Action

Inhibits cell division

Reduces toxin production

Indication

Clostridioides difficile infection

Target organisms



C. difficile


Antibiotics in DevelopmentSulbactam + 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


Hospital Acquired Bacterial Pneumoniae

Ventilator Associated Bacterial Pneumoniae

Target organisms

ESKAPE pathogens

A. baumannii


CRAB



Sulopenem & sulopenem-etzadroxil-probenecid

Current Status

Phase 3

Class

β-lactam (carbapenem)

Mechanism of Action


Indication

Prostatitis


Complicated intra-abdominal infections

Complicated UTI

Gonococcal urethritis

Pelvic inflammatory disease

Uncomplicated UTIhttps://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development


Sulopenem & sulopenem-etzadroxil-probenecid

Target organisms

ESKAPE pathogens

K. pneumoniae, Enterobacter spp.


ESBL producing organisms



Antibiotics in DevelopmentSolithromycin

Current Status

Phase 3

Class

Macrolide

Mechanism of Action

Inhibits bacterial protein synthesis

Targets the bacterial 50S ribosomal subunit

Indication


Uncomplicated urogenital gonorrhea

Target organisms





Antibiotics in DevelopmentTebipenem & tebipenem pivoxil hydrobromide

Current Status

Phase 3

Approved for use in Japan (Orapenem®) for pneumonia, otitis media, sinusitis

Class

Carbapenem

Mechanism of Action


Indication



Diabetic foot infection

Target organisms

ESKAPE pathogens

K. pneumoniae

Possibly A. baumannii, P. aeruginosa


ESBL producing organisms



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




Questions?

Assessment Questions1. 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

References1. 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.

References10. 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.

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