This document discusses recent advances in treating multidrug-resistant gram-negative bacteria. It mentions that antimicrobial resistance is a global health problem and new antibiotics are urgently needed. It then summarizes recent developments in beta-lactam antibiotics like cephalosporins, carbapenems, and monobactams. Newer cephalosporins discussed include cefiderocol and cefepime/AAI101, which are undergoing clinical trials. Ceftobiprole is another newer cephalosporin marketed in Europe. Sulopenem is a novel oral and IV penem antibiotic in development.

1. RECENT ADVANCES IN
MANAGEMENT OF
MULTIDRUG RESISTANT
GRAM-NEGATIVE
ORGANISMS
Shreya Gupta

2. FLOW OF PRESENTATION
• Introduction: Antimicrobial Resistance
• Global Antimicrobial Resistance Surveillance System (GLASS)
• WHO Priority list for R & D 2017
• Gram Negative bacteria: Classification, Treatment
• Drug Resistant GNB: Causes and risks
• Need for new antibiotics
• Recent advances in Beta lactam antibiotics
• Recent advances in aminoglycosides, tetracyclines,
fluoroquinolones
• Investigational new groups
• Existing challenges
• Preventive strategies for antibiotic resistance

3. • Antimicrobial resistance (AMR) is the ability of a
microorganism (like bacteria, viruses, and some parasites)
to stop an antimicrobial (such as antibiotics,
antimalarials) from working against it.
https://www.who.int/antimicrobial-resistance/en
According to the latest AMR report released by UN WHO,
• Currently, at least 700,000 people die each year due to
drug-resistant diseases
• By 2030, antimicrobial resistance could force up to 24
million people into extreme poverty.
ANTIMICROBIAL RESISTANCE

4. • Antibiotic resistance “could cause 10 million deaths
each year by 2050”, complicating routine treatment for
infections and minor medical procedures
https://www.who.int/antimicrobial-
coordinatio group/IACG_final_report_EN.pdf?ua=1
ANTIMICROBIAL RESISTANCE

5. India carries one of the largest burdens of drug-resistant
pathogens worldwide,
• Highest burden of multidrug-resistant tuberculosis
• Alarmingly high resistance among Gram-negative and
Gram-positive bacteria
• Bacterial sepsis, acute respiratory illness, and acute
diarrheal diseases are leading killers of children under 5
years of age.
• Causes:
Lacking public health infrastructure,
High burden of disease
Unregulated sales of antibiotics.
ANTIMICROBIAL RESISTANCE-
INDIAN SCENARIO

6. India is one of the largest consumers of antibiotics worldwide,
with antibiotic sales continuing to increase rapidly.

7. • Launched in October 2015 by WHO as part of the
implementation of the Global Action Plan on
Antimicrobial Resistance (AMR)
• Aim is to support global surveillance and research
in order to strengthen the evidence base on
informed decision-making and drive national, regional,
and global actions.
• Epidemiological and microbiological information
combined,
To understand extent and impact of AMR on populations
To monitor trends and detect emerging resistance
To measure the effectiveness of interventions to control
AMR.
Global Antimicrobial Resistance
Surveillance System (GLASS)

8. 8 priority bacteria included in GLASS:
• Escherichia coli
• Klebsiella pneumoniae
• Acinetobacter spp.
• Salmonella spp.
• Shigella spp.
• Neisseria gonorrhoeae
• Staphylococcus aureus
• Streptococcus pneumoniae
Global Antimicrobial Resistance
Surveillance System (GLASS)

9. WHO PRIORITY LIST FOR R&D 2017
PRIORTY3:MEDIUM
PRIORITY2:HIGH
PRIORITY1:CRITICAL
•Acinetobacter
baumannii,
carbapenem-
resistant
Pseudomonas
aeruginosa,
carbapenem-
resistant
Entero-
bacteriaceae,
carbapenem-
resistant,
3rd generation
cephalosporin-
resistant
E. faecium,
VRE.
S. aureus,
MRSA,
vancomycin
resistant
H. pylori,
clarithromycin-
resistant
Campylobacter,
FQ resistant
Salmonella spp.,
FQ resistant
N. gonorrhoeae,
3rd gen cephalosporin-
resistant, FQ-resistant
Streptococcus
pneumoniae,
penicillin-non-
susceptible
Haemophilus
influenzae,
ampicillin-
resistant
Shigella spp.,
FQ-resistant

10. GRAM
NEGATIVE
BACTERIA AND
INFECTIONS

12. ORGANISM COMMON INFECTIONS
E. coli • Gastroenteritis, UTIs (most common)
• Pelvic inflammatory disease
• Meningitis in newborn
• Bloodstream infections
Klebsiella
Serratia
Enterobacter
Infections in hospitals or in long-term care facilities,
• Urinary or respiratory tract (pneumonia, bladder or kidney infections)
infections)
• I/V Catheter associated infections
• Burns
• Surgical site infection
• Bloodstream (bacteremia or sepsis)
Pseudomonas
aeruginosa
Skin and soft-tissue infections
• Burns leading to bacteraemia
• Deep puncture wounds of the foot : Draining sinuses, cellulitis, and
and osteomyelitis
Acute otitis externa
Ventilator-associated pneumonia
Nosocomial UTI
Acute bacterial endocarditis
Acinetobactor
baumanii
Nosocomial infections,
• Aspiration pneumonia
• Catheter-associated bacteraemia
• Wound and suture line
infections
• Prostatitis
• Gallbladder infection

13. BACTERIA DRUGS USED COMMONLY
1. E coli
Klebsiella
Proteus
Cephalosporin (1st or 2nd generation), TMP-SMZ
Quinolone, aminoglycoside
2. Enterobacter
Citrobacter
Serratia
TMP-SMZ, quinolone, carbapenem
Antipseudomonal penicillin, aminoglycoside, cefepime
6. Pseudomonas
aeruginosa
Antipseudomonal penicillin + aminoglycoside
Antipseudomonal penicillin ± quinolone, cefepime, ceftazidime,
ceftazidime, antipseudomonal carbapenem, or aztreonam ±
aminoglycoside
9. N. gonorrhoeae Ceftriaxone, cefixime
Spectinomycin, azithromycin
10. N. meningitidis Penicillin G
Chloramphenicol, ceftriaxone, cefotaxime
3. Shigella Quinolone
TMP-SMZ, ampicillin, azithromycin, ceftriaxone
5. Salmonella Ceftriaxone , Quinolones
Chloramphenicol, ampicillin, TMP-SMZ

14. • E. coli: Uncomplicated and Complicated UTI
• Acinetobacter baumanii : Healthcare associated infections, resistant
wound infections in military personnel
• Pseudomonas aeruginosa: Bloodstream infections and pneumonia
in hospitalized patients
• Klebsiella pneumoniae: Majority healthcare-associated infections,
including pneumonia, UTIs, and bloodstream infections
• Neisseria gonorrhoeae: Gonorrhoea (2nd most commonly reported
infectious disease in the United States)
https://www.niaid.nih.gov/research/gram-negative-bacteria
DRUG RESISTANT GNB

15. GRAM NEGATIVE INFECTIONS
Risk factors for infection with resistant Gram-negative
pathogens:
• Substantial previous broad-spectrum antimicrobial
therapy
• Prolonged hospitalization
• Multiple invasive interventions
• Long term dialysis
• Mechanical ventilation
• Immunocompromised state
• Previous infection with a resistant Gram-negative

17. • Antimicrobial resistance is a global health emergency
that will seriously jeopardize progress in modern
medicine
• MDR Gram Negative bacteria cause extremely serious
infections that can kill patients in a matter of days
because of dearth of line of defence
• Most of the drugs currently in the clinical pipeline are
modifications of existing classes of antibiotics and may
offer only short-term solutions
• Need for better oral antibiotic formulations, essential
for treating infections outside hospitals or in resource-
limited settings
NEED FOR NEW ANTIBIOTICS

18. RECENT ADVANCES IN
BETA LACTAM
ANTIBIOTICS
1. CEPHALOSPORINS
2. CARBAPENEMS
3. MONBACTAMS
4. BETA LACTAMASE INHIBITORS
5. FDCs

19. BETA LACTAM RESISTANCE

20. ` BETA LACTAMASES
CLASS A
Carbapenemases
ESBLs
SERINE BETA LACTAMASES CLASS B: METALLO BETA
LACTAMASES
CLASS C:
AmpC/Cephalosporinases
Produced by Serratia,
Pseudomonas, Acinetobacter,
Citrobacter, and Enterobacter
CLASS D
Oxacillinases

21. First Generation
1. Cefazolin , cephalexin
2. Skin and soft tissue infections
3. Some activity against E.coli,
Klebsiella
Second Generation
1. Cefuroxime, cefaclor, cefoxitin
2. Upper RTI, Gynae infections,
perioperative prophylaxis
3. Good activity: H. influenzae,
Proteus, E.coli, Proteus
Third Generation
1. Ceftriaxone, ceftazidine,
cefotaxime
2. CAP, meningitis, UTI
3. Excellent activity: E.coli,
H. nfluenzae, Proteus, Klebsiella,
Serratia, Neisseria
Fourth Generation
1. Cefepime
2. Good activity against: P
aeruginosa, Enterobacteriaceae,
Haemophilus and Neisseria
3. Used in patients presenting with
febrile neutropenia,
Fifth Generation
1. Ceftaroline
2. Broad spectrum
3. Used for SSS!, CAP
4. No activity against Pseudomonas

22. NEWER CEPHALOSPORINS
1) CEFIDEROCOL
• Novel injectable siderophore cephalosporin antibiotic
• Catechol moiety on the 3-position side chain, enables ferric iron
iron ion binding
• Resulting complex of cefiderocol and iron ions is actively
transported into bacteria via ferric iron transporter systems with
with subsequent inhibition of cell wall synthesis
• Action:
Carbapenem-resistant Enterobacteriaceae
MDR P. aeruginosa and A. baumannii

23. • CURRENTLY UNDERGOING PHASE III TRIAL:
Investigator Driven Randomized Controlled Trial of
Cefiderocol Versus Standard Therapy for Healthcare
Associated and Hospital Acquired Gram-negative Blood
Stream Infection
• Estimated study completion by 2022
NEWER CEPHALOSPORINS

24. NEWER CEPHALOSPORINS
2) CEFEPIME/ AAI101
• Cefepime: 4th generation cephalosporin
• AAI101 : ESß-lactamase and carbapenamase inhibitor
that exhibits potent in vitro and in vivo activity against
many resistant Gram-negative pathogens
• Granted Fast Track Designation by the US FDA
• CURRENTLY UNDERGOING PHASE II TRIAL:
Randomized, Double-Blind, Multi-Center Study of
Cefepime/AAI101 in Hospitalized Adults With
Complicated Urinary Tract Infections, Including Acute
Pyelonephritis
• Results are pending

25. ç
NEWER R
3) CEFTOBIPROLE
• Currently marketed in Europe (not approved by USFDA)
for:
1. ABSSSI
2. Bacteraemia
3. CAP
4. Hospital-acquired bacterial pneumonia
• CURRENTLY UNDERGOING PHASE III TRIAL:
Randomized, Double-blind, Multicenter Study to Establish
the Safety and Efficacy of Ceftobiprole Compared With
Vancomycin Plus Aztreonam in the Treatment of Acute
Bacterial Skin and Skin Structure Infections
NEWER CEPHALOSPORINS

26. • Doripenem, ertapenem, imipenem, and meropenem are
licensed for use in the USA.
• Imipenem, doripenem, meropenem have wide spectrum with
with good activity against most Gram-negative rods, including
including P aeruginosa, Gram-positive organisms, and
anaerobes.
• Ertapenem does not have appreciable activity against P
aeruginosa and Acinetobacter
• Resistance: stable against most β-lactamases except
carbapenemases or metallo-β-lactamases
lactamases
CARBAPENEMS

27. SULOPENEM
• Novel Thiopenem
• First oral and IV penem antibiotic demonstrating a potent
spectrum of activity against multi-drug resistant gram-negative
negative infections in both the hospital and community settings
settings
• In March 2019, Sulopenem (IV, oral) receives Fast Track
designation in USA for:
uncomplicated UTI, complicated UTI
complicated IAI
Community-acquired pneumonia
Acute bacterial prostatitis
Gonococcal urethritis and Pelvic inflammatory disease [oral]
NEWER CARBAPENEMS

28. NEWER CARBAPENEMS
CURRENTLY UNDERGOING PHASE III TRIALS: SURE 2 AND 3
• Sulopenem for Resistant Enterobacteriaceae (SURE) 2, IV
sulopenem followed by oral sulopenem combined with
probenecid in a bilayer tablet (oral sulopenem) will be compared
compared to IV ertapenem followed by oral ciprofloxacin in
adults with complicated urinary tract infections (cUTI).
• SURE 3, IV sulopenem followed by oral sulopenem is compared
compared to IV ertapenem followed by a combination of oral
oral ciprofloxacin and oral metronidazole in adults with
complicated intra-abdominal infections (cIAI)

29. SPR994
• Oral formulation of tebipenem antibiotic for treatment of cUTI
and acute pyelonephritis
• FDA has granted fast track status for SPR994, in March 2019
2019
• Potent antibiotic activity against Gram-negative bacteria,
including E. coli-producing ESBL and ESBL-producing Klebsiella
NEWER CARBAPENEMS

30. • CURRENTLY UNDERGOING Phase 3 trial: ADAPT-PO [(A
Phase 3, Randomized, Double-blind, Double-dummy,
Multicenter, Prospective Study to Assess the Efficacy, Safety
Safety and Pharmacokinetics of Orally Administered
Tebipenem Pivoxil Hydrobromide (SPR994) Compared to
Intravenous Ertapenem in Patients with Complicated Urinary
Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)
NEWER CARBAPENEMS

31. • Spectrum of activity : limited to aerobic Gram-
negative organisms
aeruginosa)
• No activity against Gram-positive bacteria or anaerobes.
• Aztreonam is the only monobactam currently available
USA.
• Resistance: Stable to many β-lactamases except AmpC β-
lactamases and ESBL
MONOBACTAMS

32. NEWER MONOBACTAMS
LYS228/BOS 228
• Activity against Complicated urinary tract infections and
complicated intra-abdominal infection
• Demonstrated activity against carbapenem resistant
enterobacteracieae (CRE) with resistance caused by serine
beta-lactamases (SBLs) and/or metallo beta-lactamases (MBLs)
(MBLs)
• CURRENTLY UNDERGOING PHASE II TRIAL: Randomized,
Randomized, Controlled, Evaluator-blinded, Multi-center Study to
to Evaluate LYS228 Pharmacokinetics, Clinical Response, Safety, and
Safety, and Tolerability in Patients With Complicated Intra-
abdominal Infection

33. BETA LACTAMASES
• MOST COMMON: Inactivation of β-lactam antibiotic by β-
lactamase
• AmpC β-lactamase produced by Pseudomonas
Enterobacter sp
• Extended-spectrum β-lactamases (ESBLs) in
hydrolyze both cephalosporins and penicillins
• Carbapenems are highly resistant to hydrolysis by
penicillinases and cephalosporinases, but they are
hydrolyzed by metallo-β-lactamases and
carbapenemases

34. NEWER BETA LACTAMASE INHIBITORS
SECOND GENERATION β- LACTAMASE INHIBITORS
• Non-β-lactam (βL)-based βLIs
• Lack a β-lactam ring in their structure
• Derived from diazabicyclooctanes (DBO)
• Include avibactam, relebactam, zidebactam and nacubactam
THIRD GENERAION β-LACTAMASE INHIBITORS
• Non-βL/βLIs
• Derivative of cyclic boronate
• Include Vaborabactam

35. 1stGEN-
ERATION
2nd GENERATION 3rd GEN-
ERATION
Clavulanic
acid/
Sulbactam/
Tazobactam
m
Avibactam
(first gen
DBO)
Relebactam
(First gen
DBO)
Zidebactam
(2nd Gen
DBO)
Nacubactam
(2nd Gen DBO)
DBO)
Vaborabactam
Derived
from β-
lactam
scaffolds
Non-β-lactam (βL)-based βLIs
derived from DBO heterocyclic core structure
Boronic acid
derivative
• Covers
only
Class A
• Inactive
against
class C,D
• Irreversible binding
• Potent inhibitors of Class
Class A,C,D
• No activity against
Acinetobactor producing
producing
carbapenemases and MBL
MBL producers
• Increased activity to Class
Class C, more than 1st gen
gen DBOs
• Potent activators of P.
aeruginosa PBP2 and A.
baunanii PBP2
Potent inhibitor
inhibitor of class
class A (KPC),
and class C
Sulbactam
has intrinsic
intrinsic
activity
No useful intrinsic activity Intrinsic activity against P.
aeruginosa and A. baunanii

36. ESBL KPC MBL Amp C MDR PA MDR Ab
Phase 1 Cefepime +
Zidebactam
+ + + + +/- +
Phase 1 Cefepime+
VNRX5133
+ + + + + -
Phase 1 Meropenem
+Nacubactam
+ + - + + -
Phase 3
3
Meropenem+
vaborabactam
+ + - + - -
Phase 3
3
Cefepime +
AAI101
+ + - + - -
Phase 3
3
Imipenem/
cilastatin +
Relebactam (MK-
7655A)
+ + - + - -
FDCs UNDER DEVELOPMENT

37. RECENT ADVANCES
IN
1.TETRACYCLINES
2.AMINOGLYCOSIDES
3.FLUOROQUINOLONES

38. ER
TETRACYCLINES
• Bacteriostatic
• GRAM NEGATIVE SPECTRUM:
H. ducreyi
H. pylori
Yersinia sp.
Campylobacter
Pasturella
Calymmatobacterium
V. cholerae

39. ER
TETRACYCLINE RESISTANCE
Klebsiella
Salmonella typhi
Enterobacteriaceae
Proteus sp.
Pseudomonas
Impaired influx or increased efflux by
an active transport protein pump
Tet(AE) efflux pump
Ribosome protection due to production
production of proteins that interfere
with tetracycline binding to ribosomeEnzyme inactivation
Efflux pumps
for
Tigecycline
too

40. 1) OMADACYCLINE
• Modified minocycline
• Spectrum :
A. ESBL producing E.coli
B. MRSA
C. MDR S. pneumoniae
• Not active against: ESBL producing K. pneumoniae,
Ceftazidime resistant Enterobacter
NEWER TETRACYCLINES

41. Approval : CAP and acute bacterial SSSI by USFDA in October 2018
Other potential indications: complicated and uncomplicated UTI
• Approval : Oct. 2, 2018 (U.S. FDA) for CAP and Acute
bacterial SSSI
• Clinical trials:
a) OPTIC (Omadacycline for Pneumonia Treatment in the
Community) trial: Phase 3 Randomized, Double-Blind,
Multi-Center Study to Compare the Safety and Efficacy of
Omadacycline IV/Oral to Moxifloxacin IV/Oral for Treating
Adults Subjects With CAP
b) OASIS Trial: Phase 3 Randomized, Double-Blind, Multi-
Center Study to Compare the Safety and Efficacy of Oral
Omadacycline to Oral Linezolid for Treating Adult Subjects
With ABSSSI
NEWER TETRACYCLINES

42. DOSAGE REGIMEN OMADACYCLINE
CABP Day 1: 200 mg by intravenous
infusion over 60 minutes OR 100 mg
mg by intravenous infusion over 30
30 minutes twice
100 mg by
intravenous infusion
over 30 minutes once
once daily OR 300 mg
mg orally OD
ABSSSI Day 1: 200 mg by intravenous
infusion over 60 minutes OR 100 mg
mg by intravenous infusion over 30
30 minutes twice
100 mg by
intravenous infusion
over 30 minutes once
once daily OR 300 mg
mg orally OD
ABSSSI Day 1 and Day 2: 450 mg orally OD 300 mg orally OD
NEWER TETRACYCLINES

43. SIDE EFFECTS:
• Hypersensitivity Reactions
• Tooth Discoloration
• Inhibition of Bone Growth
• Clostridium difficile-Associated Diarrhea (CDAD)
NEWER TETRACYCLINES

44. ER
NEWER TETRACYCLINES
2) ERAVACYCLINE
• Structural similarity to tigecycline, chemical modifications
• Oral bioavailability of >90% in healthy volunteers
• Action:
1. MDR Enterobacteriacea
2. A. baumannii
3. Enterococcus faecalis, Enterococcus faecium
4. Staphylococcus aureus
5. Clostridium perfringens
6. Bacteroides species

45. Approval : CAP and acute bacterial SSSI by USFDA in October 2018
Other potential indications: complicated and uncomplicated UTI
• Approval: Aug. 27, 2018 (U.S. FDA) for cIAI infections
• Clinical trial: Assessing the Efficacy and Safety of
Eravacycline vs Ertapenem in Complicated Intra-abdominal
Infections in the Investigating Gram-Negative Infections
Treated With Eravacycline (IGNITE 1) Trial: A
Randomized Clinical Trial
• Failed to show superiority over ertapenem for cUTI in
IGNITE 3 Phase III study
NEWER TETRACYCLINES

46. DOSAGE REGIMEN:
• 1 mg/kg every 12 hours I/V only
• Recommended duration of treatment for cIAI is 4 to 14 days
SIDE EFFECTS:
• Hypersensitivity Reactions
• Tooth Discoloration
• Inhibition of Bone Growth
• Clostridium difficile-Associated Diarrhea
NEWER TETRACYCLINES

47. AMINOGLYCOSIDES
• Bactericidal
• Require oxygen for entry into cell
• Active against all aerobic Gram negative bacteria
• No activity against anaerobes
• Commonly used: Gentamicin, Tobramycin, and
Amikacin

48. Enterobacteriaceae
Klebsiella
Pseudomonas
Mutated receptor protein on 30S
ribosome
Production of AG Modifying Enzymes
Enzymes that inactivate by
adenylation, acetylation, or
phosphorylation
Impaired entry:
1. mutation/deletion of a porin protein
protein
2. oxygen-dependent transport process
process is not functional
AMINOGLYCOSIDE RESISTANCE

49. NEOGLYCOSIDES
PLAZOMICIN
• Sisomycin derivative
• Action:
1. ESBL producing Enterobacteriaceae
2. CRE
3. KPC
4. MDR P. aeruginosa, MDR A. baumanii
• Not inhibited by most aminoglycoside modifying enzymes
(AMEs) known to affect gentamicin, amikacin and tobramycin
tobramycin
• Reduced activity against Enterobacteriaceae that overexpress
efflux pumps or lower expression of porins

50. • Approval : June 26, 2018 (U.S. FDA) for Complicated
urinary tract infections including acute
• DOSAGE: 15 mg/kg I/V once daily
• Other potential indications:
Hospital-acquired bacterial pneumonia
Ventilator Associated Pneumonia
Complicated intra-abdominal infections
• Suggested combination with ceftazidime-avibactam for
better efficacy against KPC producers
NEOGLYCOSIDES

51. WARNING: NEPHROTOXICITY, OTOTOXICITY, NEUROMUSCULAR
BLOCKADE and FETAL HARM
• Risk of nephrotoxicity. Greater risk in patients with impaired
impaired renal function, elderly, concomitant nephrotoxic
medications. Assess creatinine clearance in all patients prior to
to and during therapy
• Ototoxicity, manifested as hearing loss, tinnitus, and/or vertigo,
vertigo, has been reported
• Monitor for adverse reactions associated with neuromuscular
neuromuscular blockade, particularly in high-risk patients with
with underlying neuromuscular disorders (including myasthenia
myasthenia gravis) or in patients concomitantly receiving
neuromuscular blocking agents
• Fetal harm when administered to a pregnant woman
NEOGLYCOSIDES

52. FLUOROQUINOLONES
Active against:
• Gram negative bacilli causing urinary and GI infections
• Ciprofloxacin is the most active agent of this group
Gram-negative organisms, particularly P aeruginosa
• Some gram positive organisms
• Bactericidal

53. P aeruginosa
Serratia marcescens
Staphyloccocci
1/more point mutations in the quinolone
binding region or to a change in the
permeability of organism
Variant of an aminoglycoside
acetyltransferase capable of
modifying ciprofloxacin
Plasmid encoded, Qnr proteins,
proteins, which protect DNA
gyrase from fluoroquinolones
FLUOROQUINOLONE RESISTANCE

54. NEWER FLUOROQUINOLONES
1) FINAFLOXACIN
• Higher potency against ESBL producing E.coli and K.pneumoniae

55. • Completed trial: Explorative Randomized Phase II Clinical Study of
the Efficacy and Safety of Finafloxacin versus Ciprofloxacin for
Treatment of Complicated Urinary Tract Infections
• RESULTS:
Suggests that finafloxacin given for 5 days is viable treatment option
option for the rapid resolution of major signs and symptoms of cUTI
NEWER FLUOROQUINOLONES

56. NEWER FLUOROQUINOLONES
2) DELAFLOXACIN
Approval: 2017 (U.S. FDA) for the treatment of acute
bacterial SSSI caused by susceptible isolates of the
E. coli
Enterobacter cloacae
K. pneumoniae
P. aeruginosa
MRSA
S.pyogenes
Enterococcus fecalis

57. NEWER FLUOROQUINOLONES
DOSAGE:
• 300 mg by intravenous infusion over 60 minutes, every 12
hours, or
• 450-mg tablet orally every 12 hours for 5 to 14 days total
duration
BOX WARNING:
WARNING: SERIOUS ADVERSE REACTIONS
INCLUDING TENDINITIS, TENDON RUPTURE,
PERIPHERAL NEUROPATHY, CENTRAL NERVOUS
SYSTEM EFFECTS, and EXACERBATION OF
MYASTHENIA GRAVIS

58. INVESTIGATIONAL
NEW GROUPS OF
ANTIMICROBIALS
1. ANTIMICROBIAL PEPTIDE MIMETIC
2. ARYLOMYCIN DERIVATIVES
3. ANTIBIOTIC HYBRIDS

59. • First in class of Outer Membrane 52 Protein
Targeting Antibiotics (OMPTAs)
• Binds to lipopolysaccharide transport protein D
outer membrane protein involved in lipopolysaccharide
biogenesis in Gram -negative bacteria
• Inhibits the LPS transport function of LptD and
lipopolysaccharide alterations in the outer membrane of
the bacterium, leading to cell death
• Pathogen-specific antibiotic
• INDICATION: hospital-acquired pneumonia (HAP) and
ventilator-associated pneumonia (VAP)
caused by Pseudomonas aeruginosa
ANTIMICROBIAL PEPTIDE MIMETIC:
MUREPAVADIN

60. • CURRENT STATUS: PHASE III Multicenter, Open-label,
Randomized, Active-controlled, Parallel Group, Pivotal
Study to Investigate the Efficacy, Safety and Tolerability,
and Pharmacokinetics of Murepavadin Combined With One
Anti-pseudomonal Antibiotic Versus Two Anti-
pseudomonal Antibiotics in Adult Subjects With Ventilator-
associated Bacterial Pneumonia Suspected or Confirmed to
be Due to Pseudomonas Aeruginosa
• RESULTS: Pending
ANTIMICROBIAL PEPTIDE MIMETIC:
MUREPAVADIN

61. ARYLOMYCIN DERIVATIVES
• Macrocyclic Lipopeptides
• Inhibit the bacterial type I signal peptidase
(SPase): membrane-bound protease that cleaves signal
sequences of proteins following their translocation
across the cytoplasmic membrane
• UNDER DEVELOPMENT: G0775, Synthetic
derivative. Potent in vitro antibacterial activity against:
 E.coli
 Klebsiella
16 highly MDR strains of A. baumannii
12 highly MDR strains of P. aeruginosa

62. ANTIBIOTIC HYBRIDS
• Molecular hybrids by fusing different biologically
active agents into one heteromeric entity with the hope of
retaining the biological actions of the constituent fragments.
• Molecular linker/tether is often used to link the
participating agents together via a covalent bond, molecules
could also be fused together directly
• Hybridization may enhance the efficacy or even impart a
new mechanism of antibacterial action to the resulting
hybrid agent.
• In vitro study: Tobramycin-based hybrids as
potentiate antibiotics against Pseudomonas

64. EXISTING CHALLENGES
1. Regulation: Communication, harmonization and
standardization needed, policymakers need to sit together
together and agree on a common set of rules
2. Sharing of information: Data about resistant strains and the
usefulness of antibiotics should be made available in real
time, a “smart antibiogram” could be developed to guide
treatment.
3. Cost: Biggest obstacle. Modern diagnostics tend to be more
expensive to develop and use, what we now regard as too
much of an investment will seem comparatively cheap under
under dire circumstances.

65. PREVENTIVE STRATEGIES FOR
ANTIBIOTIC RESISTANCE
• Curtail production, prescription and consumption of antibiotics
both in human and in veterinary medicine
• Implementing a mandatory antibiotic stewardship regimen

66. • Principle of rapid diagnosis, quick transmission of
information, quick treatment: Alert or flagging system
and electronic recording of MDRO carriers in patient
charts/patient database), appropriate information of
caregivers, patients, visitors and all hospital personnel
• Monitoring and reinforcing infection control
standard precautions
• Frequent hand-washing and cautionary measures by
workers
• Discarding secretions/body fluids in designated areas
cleaning sinks (not in hand wash sinks)
• Patient education: toilet use, emptying of urinary bags,
• Safe disposal of (hospital) waste
PREVENTIVE STRATEGIES FOR
ANTIBIOTIC RESISTANCE

67. DEVELOPMENT DRUG CLASS/GROUP
FDA APPROVED Omadacycline Tetracycline
FDA APPROVED Eravacycline Tetracycline
FDA APPROVED Plazomicin Neoglycoside
FDA APPROVED Delafloxacin Fluoroquinolone
Phase 3 Cefepime + AAI101 β-lactam (cephalosporin) + β-
lactamase inhibitor (β-lactam)
Phase 3 Murepavadin Antimicrobial peptide mimetic
Phase 3 Sulopenem Carbapenem
Phase 3 Cefiderocol Cephalosporin
Phase 3 Imipenem/ cilastatin +
relebactam (MK-
7655A)
β-lactam (carbapenem) + β-
lactamase inhibitor
(diazabicyclooctane)
Phase 3 SPR994 Carbapenem
SUMMARY

68. DEVELPOMENT DRUG CLASS/GROUP
Phase 2 ETX2514SUL β-lactam (sulbactam) + β-
lactamase inhibitor (DBO)
Phase 2 BOS-228 (LYS228) Monobacam
Phase 2 Finafloxacin Fluoroquinolone
Phase 1 Cefepime + VNRX-
5133
β-lactam (cephalosporin) +
β-lactamase inhibitor (cyclic
boronate)
Phase 1 Cefepime + zidebactam β-lactam (cephalosporin) + β-
lactamase inhibitor (DBO)
Phase 1 ETX0282CPDP β-lactam (cephalosporin) + β-
lactamase inhibitor (DBO)
Phase 1 Meropenem
+Nacubactam
β-lactam (carbapenem) + β-
lactamase inhibitor (DBO)
Phase 1 SPR206 Polymyxin
Phase 1 TP-6076 Tetracycline

69. Thank You

70. • Jean SS, Gould IM, Lee WS, Hsueh PR. New Drugs for Multidrug-Resistant Gram-
Negative Organisms: Time for Stewardship. Drugs. 2019 Apr 10:1-0.
• Peleg AY, Hooper DC. Hospital-acquired infections due to gram-negative bacteria.
New England Journal of Medicine. 2010 May 13;362(19):1804-13.
• https://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-
bacteria-for-which-new-antibiotics-are-urgently-needed
• Martelli G, Giacomini D. Antibacterial and antioxidant activities for natural and
synthetic dual-active compounds. European journal of medicinal chemistry. 2018
Sep 5.
• Smith, P. A., Koehler, M. F. T., Girgis, H. S., Yan, D., Chen, Y., Chen, Y., Heise, C.
E. (2018). Optimized arylomycins are a new class of Gram-negative antibiotics.
Nature, 561(7722), 189–194.
• Dixit A, Kumar N, Kumar S, Trigun V. Antimicrobial resistance: Progress in the
decade since emergence of New Delhi metallo-β-lactamase in India. Indian Journal
of Community Medicine. 2019 Jan 1;44(1):4.
• pewtrusts.org/antibiotic-pipeline
• https://www.cdc.gov/antibiotic-use/healthcare/implementation/core-
elements.html
REFERENCES