NEWER ANTIBACTERIALS

DALBAVANCIN

  • Novel second-generation lipoglycopeptide antibiotic
  • Approved by FDA
  • Mechanism -binds to the D-alanyl-D-alanyl residue on growing peptidoglycan chains-prevents transpeptidation, transglycosylation of peptidoglycan- cell wall formation-  bactericidal effect  
  • Effective against VRE, VRSA
  • The long half-life of 150-250 hours (protein binding >90%)
  • The dosage regimen of 2 doses one week apart
  • IV infusion -(1 g followed one week later by 500 mg)

USES AND DISADVANTAGE

  • Most widely used -MRSA
  • Also used in-acute bacterial skin and skin structure infections (ABSSSIs), streptococcus pyogens (methicillin-sensitive & resistant strains)
  • Not active against vancomycin-resistant S. aureus (VRSA).  

IN PREGNANCY & LACTATION

  • Used in caution
  • No evidence in animals – teratogenicity

FUTURE DEVELOPMENT

  • Single-dose regimen
  • For use-hospitalized community-acquired pneumonia (CAP) due to MRSA and pediatric osteomyelitis

ORITAVANCIN

  • Novel semisynthetic glycopeptide antibiotic 
  • Approved by FDA
  • Mechanism of action- inhibition of transglycosylation & transpeptidation-disruption of cell wall
  • oritavancin and Telavancin disrupt the membrane potential and thus increase cell permeability causing rapid bactericidal activity
  • long half-life of about 250 hours (about 90% protein binding)
  • Single-dose regimen -1.2 G IV
  • Pregnancy- Category C
  • USES
    • Used for -treatment of serious Gram-positive bacterial infections & ABSSSI
    • More effective- clostridium difficile infection

ADVANTAGES OVER VANCOMYCIN

  • Longer half-life
  • Less frequent dosing
  • No known nephrotoxicity

CEPHALOSPORINS

  • Resistant Gram-negative Enterobacteriaceae –increasing
  • To fix this problem-

1. New cephalosporins + beta-lactamase inhibitors

2. Old  cephalosporin + new beta-lactamase inhibitors

Ceftaroline

  • New  5th-generationcephalosporin
  • Broad-spectrum Beta-lactam antimicrobial agent
  • Effective against  MRSA, VISA, VRSA, Cephalosporin resistant S.Pneumonia.
  • Has potent bactericidal activity by binding to PBP (inhibits transpeptidation & cell wall synthesis)
  • Exhibits- bind to (PBPs1-4))
  • greater binding affinity than the other cephalosporins for PBP2a (MRSA)
  • Developed by modifying the structure of the fourth generation cephalosporin Cefozopran.
  • IV dose-600 mg every 12 hours-infusion

USES

  • Low Drug interaction.
  • Used-treatment of CAP and hospital-acquired pneumonia (HAP) in adults
  • Active against-MRSA

DISADVANTAGE

  • Hydrolyzed by extended-spectrum ß-lactamases (ESBL) and AmpC beta-lactamases
  • Dose adjustments in renal  impairment
  • Side effects-Nausea, Vomiting, dysgeusia and caramel taste like taste disturbance.

CEFTOBIPROLE

  • Broad spectrum- MRSA, P.aeruginosa, Penicillin-resistant S.pneumoniae, Enterococci.
  • Stronger affinity for PBP2a of MRSA & PBP2x of S.Pneumonia
  • 500 mg iv 12 hourly

CEFTAZIDIME-AVIBACTAM – Avycaz

  • Approved by FDA – complicated intra-abdominal infections in combination with metronidazole  & UTI
  • Avibactam – extends its activity to ESBL and AmpC  producing strains & carbapenemases (KPC)

DOSAGE REGIMEN

  • 2.5 gm IV every 8 hourly
  • 2 hours infusion
  • Duration-7-14 days

DISADVANTAGE

  • Avibactam -does not protect against other resistance mechanisms (penetration, efflux)
  • ADVERSE EFFECT – Nausea, vomiting, Dizziness, Anxiety, Increase in liver enzymes

CEFTOLOZANE-TAZOBACTAM

  • New cephalosporin- against Pseudomonas
  • combination with tazobactam- effective  against Enterobacteriaceae with ESBL production
  • 1 g/0.5 g – every 8 hours by IV infusion over 1 hour

NEWER CARBAPENEMS

Doripenem

  • Parenteral carbapenem approved for the treatment of complicated urinary tract infections and intra-abdominal infections.
  •  The high binding affinity to PBP-2 and -3 may enhance its activity against drug-resistant P. aeruginosa.
  • a suitable alternative to currently available anti-pseudomonal carbapenems
  • Gram-positive cocci like imipenem and activity against gram-negative bacilli like meropenem
  • stable to ESBLs produced by E. coli and Klebsiella species and to AmpC β-lactamases enzymes;

Razupenem (PZ-601)

  • novel carbapenem active against multidrug-resistant gram-positive and gram-negative (ESBL producers) bacteria and is currently in trials for cSSSI

meropenem and vaborbactam 2017

  • combination of meropenem, a penem antibacterial, and vaborbactam, a beta-lactamase inhibitor.
  • complicated urinary tract infections


Pleuromutilin

  • Retapamulin
  • Novel topical antibiotic and the first approved member in this new class.
  • It is approved for the treatment of skin and soft tissue infections caused by S. pyogenes and S. aureus, ineffective against gram-negative organisms
  • Retapamulin is a semisynthetic pleuromutilin derivative isolated from Clitopilus scyphoides (an edible mushroom).
  • It is a protein synthesis inhibitor that acts by binding to the 50-S subunit of bacterial ribosomes.
  • Plasma protein binding of Retapamulin is 94% and it is metabolized mainly in the liver by CYP3A4 to numerous metabolites
  • The most common adverse effect is pruritus at the application site.

Telithromycin

  • It is the first ketolide to enter clinical use for the treatment of CAP, chronic bronchitis and acute sinusitis.
  • In 2010, a published report described the likely mechanism of action underlying not only the cases of liver failure but also cases of visual disturbances and exacerbations of myasthenia gravis.
  • The study showed that a pyridine moiety that is part of the telithromycin molecule acts as an antagonist on cholinergic receptors located in the neuromuscular junction, the ciliary ganglion of the eye and the vagus nerve innervating the liver.
  • Other macrolides, such as azithromycin and clarithromycin and the fluoroketolide, solithromycin, do not contain the pyridine moiety and do not antagonize these cholinergic receptors significantly.
  • FDA “black box warning,” à should not be used in patients with myasthenia gravis, a disease that causes muscle weakness.’
  • Following this decision, Sanofi-Aventis withdrew the drug from active sales in the United States.

Fidaxomicin

  • Alternative to Vancomycin and Metronidazole against CDI.
  • Trial – Non inferior to Vancomycin
  • Recurrence rates of CDI lower
  • 200 mg oral dose twice daily.

Omadacycline

  • modernized tetracycline specifically designed to overcome tetracycline resistance.
  • community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections
  • Adult patients with community-acquired bacterial pneumonia (CABP) caused by the following susceptible microorganisms: Streptococcus pneumonia, Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae.
  • Adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by the following susceptible microorganisms: Staphylococcus aureus (methicillin-susceptible and -resistant

isolates), Staphylococcus lugdunensis, Streptococcus pyogenes, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Enterococcus faecalis, Enterobacter cloacae, and Klebsiella pneumoniae.

Eravacycline

  • tetracycline-class antibacterial.
  • complicated intra-abdominal infections
  • supplied as a solution for intravenous administration. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Xerava and other antibacterial drugs, Xerava should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
  • The recommended dose regimen of Xerava is 1 mg/kg every 12 hours. Administer intravenous infusions over approximately 60 minutes every 12 hours.
  • The recommended duration of treatment with Xerava for cIAI is 4 to 14 days.
  • The duration of therapy should be guided by the severity and location of infection and the patient’s clinical response.

Plazomicin

  • aminoglycoside antibacterial.
  • complicated urinary tract infections
  • specifically indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis caused by the following susceptible microorganism(s): Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae.
  • supplied as a solution for intravenous infusion.
  • To reduce the development of drug-resistant bacteria and maintain the effectiveness à should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
  • recommended dosage regimen à 15 mg/kg administered every 24 hours by intravenous (IV) infusion over 30 minutes in patients 18 years of age or older and with creatinine clearance (CLcr) greater than or equal to 90 mL/min.
  • The duration of therapy should be guided by the severity of the infection and the patient’s clinical status for up to 7 days.
  • During treatment, dosage adjustments may be required based on the change in renal function.

Delafloxacin

  • fluoroquinolone antibacterial.
  • acute bacterial skin and skin structure infections
  • indicated for use in adults for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following:
  • Gram-positive organisms: Staphylococcus aureus (including MRSA], Staphylococcus haemolyticus, Streptococcus agalactiae, Streptococcus pyogenes, and Enterococcus faecalis.
  • Gram-negative organisms: Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa

Black Box Warning:

  • Tendinitis and tendon rupture,
  • Peripheral neuropathy,
  • may exacerbate muscle weakness in patients with myasthenia gravis. Avoid in patients with a known history of myasthenia gravis.

Ozenoxacin

  • quinolone antimicrobial.
  • specifically indicated for the treatment of impetigo due to Staphylococcus aureus or Streptococcus pyogenes in adult and pediatric patients 2 months of age and older.
  • supplied as an ointment for topical administration

Oxazolidinone

  • Linezolid -oxazolidinone available in the market for the treatment of gram-positive infections, including those caused by MRSA or VRE.
  • Newer oxazolidinones with improved potency, aqueous solubility, and reduced toxicity –by modifications of A, B and C rings of linezolid]
  • Approved by FDA for the treatment of cSSSI and uSSSI respectively, completed phase II clinical trials.
  • Activated form – inhibits protein synthesis by binding to the 23-s portion of 50S ribosomal subunit of bacteria- bacteriostatic activity
  • Torezolid is the active moiety of the prodrug, torezolid phosphate,-4-16 fold greater potency than linezolid against gram-positive species including MRSA.
  • Has higher binding affinity & longer half-life
  • Resistance to linezolid results from mutations in ribosomal RNA (rRNA) that has been overcome by newer oxazolidinones by additional hydrogen bond interactions with 23-S rRNA.
  • Dose-200 mg once daily for 6 days(linezolid-600mg bd-10days)
  • Available in oral and intravenous forms

Uses

Used in –SSSI caused by streptococcus pyogenes, MRSA

More effective- enterococcus faecalis

Side effects

  • Peripheral & optic neuropathy
  • Haematological side effects(treated >6 days)
  • Nausea, vomiting
  • Headache, dizziness

Glycylcyclines- Tigecycline

  • A new class of antimicrobials –chemical derivatives of minocycline.
  • Approved by FDA for cSSTIs, intraabdominal infections, and CAP.
  • Overcome Resistance mediated by acquired efflux pumps and by ribosomal protection.
  • 20 fold more efficient than tetracycline.
  • Tigecycline has a broader spectrum of activity against aerobic and anaerobic gram-negative and positive pathogens. 
  • In vitro data — very good antibacterial activity against ESBL as well.
  • Not active against P. aeruginosa, which is an important gap in its antimicrobial spectrum
  • Tissue and intracellular penetration are good. pharmacokinetics is unaffected by food, age, race, and renal disease
  • The primary route of elimination is the biliary excretion so dose adjustment is recommended in hepatic disease


Iclaprim

  • synthetic diaminopyrimidine, selective inhibitor of the enzyme dihydrofolate reductase, which is similar to trimethoprim
  •  Iclaprim is particularly potent against S. pneumoniae and S. aureus, including trimethoprim-resistant isolates
  • Iclaprim -single agent, 0.8 mg/kg 12 hourly
  • Non-inferior to Linezolid.

Bedaquiline

  • drug-susceptible, MDR and XDR mycobacterium strains, with no cross-resistance to current first-line drugs
  • bactericidal and sterilizing activity against Mycobacterium TB) and other mycobacterial species
  • Inhibition of subunit c of ATP synthase – affects bacillary energy metabolism.
  • Better sputum & cell culture conversion

Pretomanid/Delaminid

  • Kills both replicating & Non-replicating organisms.

NEWER TARGETS & STRATEGIES FOR ANTIBACTERIAL DRUG DISCOVERY

  • virulence gene regulation that controls virulence gene expression; and bacterial adhesion to host cells e.g., inhibition of the formation of pili by pilicides
  • Virulence inhibitors could target – toxin function e.g., B. anthracis lethal factor catalytic activity
  • Inhibiting β-ketoacyl-acyl-carrier-protein synthase I/II enzyme required for fatty acid biosynthesis à Platensimycin preclinical trials block enzymes involved in the condensation steps in fatty acid biosynthesis
  • Toll-like receptor activators and modulators — antimicrobial role by producing antimicrobial peptides that activates the adaptive immune response to combat the infection
  • BACTERIOPHAGE
    • (SASPs) genes
    • S. aureus-specific delivery bacteriophage
    • inactivate bacterial DNA à BACTERICIDAL
    • Advantage -high specificity for their host without any notable adverse effects or probability of emergence of resistance
    • Treatment  -osteomyelitis, skin/wound infections, UTI, and ear infection
  • BACTERIOCINS
    • Proteins secreted by bacteria in response to challenges of nutrient starvation or inter bacterial competition
    • Treatment- chronic bacterial infection
    • Eg: colicin
  • NATURAL PRODUCTS
    • Antimicrobial compounds from natural products –Effective against gm –ve bacteria
    • Actinonin , pleuromutilin, ramoplanin, and tiacumicin B (undergoing analysis)
  • BIOENHANCERS
    • No pharmacological activity at the therapeutic dose.
    • Increase the efficacy and bioavailability of the drug.
    • combining antibiotic tetracycline with loperamide enhance the efficacy of tetracycline by increasing its permeability
    • Cow urine distillate (CUD)  with rifampicin increased the activity of drug by about 5-7 times against Escherichia coli and 3-11 times against gram-positive bacteria
  • Alternative form of drug delivery methods
    • Inhaled Amikacin available as a nanoscale liposomal formulation
    • potential for the treatment of chronic P. aeruginosa lung infections in cystic fibrosis patients
    • biofilm penetration and sustained release from liposomes.

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