NEWER ANTIBIOTICS

DR . TUSHAR YELNE
 NEED FOR NEWER
ANTIBIOTICS

 High level of antibiotic resistance among

common pathogens (Relative or complete
lack of effect of antimicrobial against a
previously susceptible microbe.Increase in MIC)

 Antibiotic misuse/abuse
 12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults

Prevent Infection
1. Vaccinate Use Antimicrobials
Wisely
2. Get the catheters
out
5. Practice antimicrobial
control
Diagnose and 6. Use local data
Treat Infection 7. Treat infection, not
Effectively 8. contamination
8. Treat infection, not
3. Target the pathogen colonization
4. Access the experts 9. Know when to say “no”
to vanco
Prevent Transmission 10. Stop treatment when
infection is cured or
11. Isolate the unlikely
pathogen
12. Break the chain of
contagion
 Mechanisms of Antibiotic
Resistance
Enzymatic destruction of drug
Prevention of penetration of drug
Alteration of drug's target site
Rapid ejection of the drug
Superinfection
 What Factors Promote Antimicrobial
Resistance?
 Exposure to sub-optimal levels of
antimicrobial
 Exposure to microbes carrying resistance
genes
consequences of Antimicrobial
Resistance
 resistantto available antibiotics
 Increased cost of treatment
 OXAZOLIDINONE
Linezolid
 Inhibits protein synthesis at ribosomal
level
 Highly active against Gram positive agents
– Staphylococci (includng MRSA, MRSE) -static
– S. pneumoniae ; GAS; GBS -cidal
– Enterococcus spp. (including VRE) -static
 VRE faecium infections with bacteremia
 Nosocomial pneumonia
– MSSA, MRSA, S. pneumoniae
 Complicated SSSI
– Staphylococcus spp., Streptococcus spp.
(GAS)
 Community-acquired pneumonia
– Staph or Strep
 Availablefor both oral and i.v. use
 Renal excretion (unchanged and metabolite)
 High degree of safety; however:
– Diarrhea, nausea, thrush, headache, tongue
discoloration
– prolonged treatment (>14 d): hematological
adverse events (e.g. thrombocytopenia)
– Peripheral neuropathy
 Synercid
 Quinupristin/dalfopristin

 Fixed 30:70 ratio

 Streptograminantibiotic (isolated from
Streptomyces sp.)
 Weak individual activity, but synergistic
together
 Mechanism of Action
– inhibits bacterial protein synthesis by
irreversibly binding to different sites on the 50S
bacterial ribosomal subunit
– quinupristin inhibits peptide chain elongation
– dalfopristin interferes with peptidyl transferase
 Mechanism of resistance
– plasmid-mediated target modification
 confers resistance to macrolides, lincosamides and
quinupristin by methylation of their common binding
site
– drug-modifying enzymes or efflux
 Antimicrobial activity
– E. faecium (not E. faecalis)
bacteriostatic or slowly bactericidal
– S. aureus (including MRSA)
– S. pneumoniae (including PCN resistant)
– viridans strep and Group A Strep
– Legionella, M. pneumoniae
 Administration
– 7.5 mg/kg IV every 8-12 hours
– No renal adjustment necessary
 Distribution
– does not penetrate CNS
– eliminated primarily in bile
 Toxicities
– phlebitis (75% when given through peripheral IV)
– arthralgias/myalgias
– hyperbilirubinemia (primarily conjugated)
 Major uses
– primarily multiple-drug-resistant gram-positive
pathogens (VRE, MRSA)
– VRE
 90% clearance of bacteremia
 52% overall efficacy (clinical success and
eradication of initial pathogen)
– Complicated skin and skin structure infections
 equal to oxacillin and cefazolin
 Telithromycin
 Ketolide (i.e. a type of macrolide)
– Semisynthetic
– PO (only formulation), favorable safety profile
 High degree of Gram positive activity
– Especially: penicillin-resistant and
erythromycin-resistant S. pneumoniae
 Borderline activity against enterococci
 Mechanism of action:
– Protein synthesis inhibition
– Binds 23 rRNA on 50S subunit in presence of
erythromycin methylation (erm) resistance
gene
 Side effects:
– Diarrhea, nausea, headache, dizziness,
vomiting
 improved activity against resistant gram-positive
respiratory pathogens
 maintain activity against gram-negative
pathogens
– Haemophilus influenzae and Moraxella catarrhalis
 active against the atypical organisms
– Chlamydia pneumoniae, Legionella pneumophilia, and
Mycoplasma pneumoniae
 active against non-respiratory pathogens
– Mycobacterium avium complex, Helicobacter pylori,
anaerobes, and Toxoplasma gondii
 Daptomycin
 New class: Cyclic Lipopeptides
– Natural compound (Streptomyces roseosporus)
 Parenteral IV formulation only
– 4 mg/Kg q 24h

 Activeagainst Gram+ bacteria resistant to

methicillin, vancomycin or linezolid
 Synergy with ß-lactams & aminoglycosides
 Mechanism of action:
– binds to bacterial membranes causing a rapid
depolarization of membrane potential leading to
inhibition of protein, DNA, and RNA synthesis,
which results in bacterial cell death

– Shares mechanism with no other antibiotic

 No cross resistance demonstrated to date
 Approved for treatment of complicated
SSSI
– S. aureus (+MRSA), streptococci, enterococci

 Not indicated for treatment of pneumonia

– Low levels in broncho-alveolar lining fluid and
lung parenchyma in clinical studies
 Primarily Renal excretion
– almost unchanged dosage adjustment
 Highly (90%) protein bound
 IV formulation only
 T ½ is 8 to 9 hours in adults (once daily)
 Elevationin CPK
 Muscle pain or weakness (myopathy)
– Reversible: dosage reduction or
discontinuation

 Antibiotic-associated colitis
– Similar rate to other antibiotics
 Oritavancin and Dalbavancin
 Second generation glycopeptides
 Modification of the chemical structure of
vancomycin and teicoplanin
 More active against resistant gram
positives
 Adult clinical studies are underway
– No studies yet in children
 Demonstrated favorable in vitro activity against MSSA,
MRSA,VISA, VRSA, and linezolid-resistant S. aureus
 Also, methicillin-susceptible, methicillin-resistant, and
vancomycin-intermediate Coagulase negative
Staphylococci strains have had favorable in vitro results
 Place of therapy (no FDA approved indication at the
moment)
– Currently in phase III trials for treatment of resistant gram-
positive organisms
– Published efficacy and safety data from 2 clinical trials are
available for treatment of skin and soft-tissue infections and
catheter-related bloodstream infections
 Tigecycline
A glycylcycline
– Derived from minocycline
A very broad spectrum antibiotic
– Covers many resistant strains of Gram-positive,
Gram-negative, and anaerobic organisms
– Note active vs. Pseudomonas
 Both
in vitro and in vivo activities have been
demonstrated against MSSA, MRSA, and VISA
 Indications
– Complicated skin and skin structure infections by
 Escherichia coli
 Enterococcus faecalis (vancomycin-susceptible)
 Staphylococcus aureus (Methi-S or Methi-R)
 Streptococcus agalactiae
 Streptococcus anginosus grp.
 Streptococcus pyogenes Bacteroides fragilis
– Complicated intra-abdominal infections by
 Citrobacter freundii
 Enterobacter cloacae
 E. coli, K. oxytoca, K. pneumoniae
 Enterococcus faecalis (Vanco-S isolates only)
 Staphylococcus aureus (Methi-S or Methi-R)
 Streptococcus anginosus group
 Bacteriodes fragilis
 Clostridium perfringens
 Peptostreptococcus micros
 Cephalosporins
Ceftobiprole
 Broad-spectrum cephalosporin
Enhanced gram-positive spectrum including MRSA, VISA,
and EF
 Bactericidal
 IV with q8h – q12h dosing
 t1/2 = 3 – 4 h
 Elimination: renal
 MIC range 0.5 – 2 mg/L
 Ceftaroline
 Broad-spectrum cephalosporin
 Enhanced gram-positive spectrum, including
MRSA, VISA, and EF
 Bactericidal
 IV with q8h – q12h dosing
 t1/2 = 2 – 3 h
 Elimination: renal
 MIC range 0.5 – 2 mg/L
 New Quinolones
 Clinifloxacin, gemifloxacin,moxifloxacin

 Improved activity against Gram positives

but no improvement of the Gram negative
activity compared to ciprofloxacin
 Pazufloxacin
 Pazufloxacin is a fused tricyclic quinolone
derivative
 unique feature of the molecule imparting
potent broad spectrum activity against
gram-positive and gram-negative bacteria
including variety of resistant strains and
anaerobic bacteria.
 Pazufloxacin has shown multimodal
mechanism of action and inhibits both DNA
gyrase and topoisomerase IV enzyme, leading
to increased antibacterial spectrum. Moreover,
pazufloxacin has been shown to have DNA
antagonistic actions also
 The multimodal mechanism of action is linked
to the low potential for the development of
resistance in pazufloxacin. Moreover, it has
been shown that pazufloxacin is not affected
by efflux mechanism of resistance.
 SPECTRUM
Enterobacteriaceae, Escherichia coli,
Klebsiella, Enterobacter, Hafnia, Citrobacter,
Proteus, Providencia, Serratia, Shigella,
Salmonella, Aeromonas and Yersinia. Against
P. aeruginosa
 methicillin-resistant Staphylococcus aureus
and P. aeruginosa,
 The antibacterial activities of PZFX are superior
to those of ceftazidime (CAZ), ceftriaxone,
Imipenem/cilastatin (IPM/CS), meropenem
against6
 Methicillin resistant S. aureus (MRSA)
 Ampicillin-resistant Haemophilus influenzae,
 ESBL possessing Klebsiella pneumoniae
 Imipenem/cilastatin (IPM/CS)-resistant
Pseudomonas aeruginosa
 Adverse effects
 diarrhoea, rashes, nausea and vomiting.
There are case reports of convulsions with
the use of the molecule.
 500 mg twice a day administered as an I.V.
infusion over 30-60 minutes. Depending on
age, symptoms and severity of infection, the
dose of the drug may be reduced to 300 mg
twice a day.
 Pazufloxacin mesylate I.V. infusion is
indicated for the following infections caused
by susceptible microorganisms:
 RTIs like pneumonia and lung abscess
 UTIs like cystitis, pyelonephritis and
prostatitis
 Abdominal infections like peritonitis,
cholecystitis, liver abscess and other intra-
abdominal abscesses
 Genital infections like endometritis
 Secondary infections after injuries, burns and
post-operative
 Cidofovir
 Nucleotide analogue of deoxycytidine
monophosphate
 Inhibitory for acyclovir-resistant TK-deficient
HSV and ganciclovir-resistant CMV
 Toxicity
– nephrotoxicity (50% proteinuria, 15%
elevated creatinine)
– neutropenia (20%)
 Clinical uses:
– CMV retinitis
– acyclovir-resistant HSV
– ?PML
 Dosing
– 5mg/kg q week for 2 weeks, then every other
week
– probenicid/saline
 Newer Antifungal Agents
 Voriconazole
– Newer azole agent
– Broad spectrum against Candida & Aspergillus
 Caspofungin (Cancidas®)
– Class: echinocandins (cell wall active agents)
– Active against resistant Candida and few molds
– Used in combination with other drugs
– Recent study in PIDJ: benefit in NICU setting
 Tobramycin Inhalation
Product
 The FDA has approved a tobramycin
solution product for inhalation (TOBI,
PathoGenesis Corporation, Seattle, Wash)
for use in the treatment of Pseudomonas
aeruginosa infection in patients with cystic
fibrosis who are at least 6 years of age
 The use of inhaled tobramycin in addition
to a systemic B-lactam in patients with
pseudomonas or acinetobacter VAP.
 Risorine (new TB drug)
 It contains piperine, which inhibits auto
induction and maintains same level
throughout therapy. It also allows use of
lower dosage of rifampicin, 200 mg
instead of 450 mg and has lower gastro-
intestinal side effects.
 Proposals to Combat
Antimicrobial Resistance
 Speed development of new antibiotics
 Trace resistance data nationwide
 Restrict antimicrobial use
 Direct observed dosing (TB)
 Speed development of new antibiotics
 Track resistance data nationwide
 Restrict antimicrobial use
 Direct observed dosing (TB)
The Future of Chemotherapeutic
Agents
 Antimicrobial peptides
– Broad spectrum antibiotics from plants and
animals
 Squalamine (sharks)
 Protegrin
 Magainin (frogs)
 Antisense agents
– Complementary DNA or peptide nucleic acids that
binds to a pathogen's virulence gene(s) and
prevents transcription