This document discusses newer antibiotics and their uses. It introduces several classes of newer antibiotics, including oxazolidinones (linezolid), glycolipopeptides (daptomycin), glycopeptides (telavancin), and pleuromutilins (retapamulin). These newer drugs are effective against multidrug-resistant gram-positive pathogens like MRSA and VRE. The document reviews the mechanisms of action, indications, clinical trial results, and side effects of these newer antibiotic classes.

1. Newer Antibiotics and their Uses
Sujit Kumar Shrestha
Resident ,Pediatrics
Department of Child Health, TUTH

2. Introduction
• The need for novel antibacterials -increasing resistance to the
older ones.
• Three classes of drug-resistant bacteria are a major cause of
concern-
– Methicillin -resistantStaphylococcus aureus (MRSA),
– multidrug-resistant (MDR) and pan-drug-resistant (PDR) gram-negative
bacteria, which include strains of Acinetobacter baumannii, Escherichia coli,
Klebsiella pneumoniae, and Pseudomonas aeruginosa, and a third class
comprising of MDR and
– extensively-drug-resistant (XDR) strains of Mycobacterium tuberculosis (MDR-
TB and XDR-TB).
• Antibacterials approved for clinical use by the FDA since the
year 2000 and those in clinical trials, especially in the later
phases will be discussed.

3. Drug Resistance
• Multidrug resistance (MDR) bacteria is defined as non-susceptibility to
one or more antimicrobials on three or more antimicrobial classes, while
strains that are non-susceptible to all antimicrobials, are classified as
extreme drug-resistant strains. [Kallen AJ, Srinivasan A: Current epidemiology of multidrug-resistant
Gram-negative bacilli in the United States. Infect Control Hosp Epidemiol 2010, 31(Suppl 1):S51–S54.]
ESKAPE pathogens
• Enterococcus faecium
• Staphylococcus aureus
• Klebsiella pneumoniae
• Acinetobacter baumanii
• Pseudomonas aeruginosa
• Enterobacteriaceae

4. Need for newer antibiotics : Desperation
• Emergence bacterial resistance
• Resurgence and new infectious disease
‘Innovation gap’ is the expression that has been used to describe the lack of
novel structural classes introduced to the antibacterial armamentarium
since 1962.
Since 2000 –Only 3 new classes of antibiotics have been introduced to the
market for human use , 1 limited to topical use
Recently, IDSA supported a proGram, called “the ′10 × ′20′ initiative”, to
develop ten new systemic antibacterial drugs within 2020 through the
discovery of new drug classes, as well as to find possible new molecules
from already existing classes of antibiotics

5. Antibiotics approval Time line

6. Acronyms
• MRSA- Methicillin resisant Staph Aureus
• VISA- Vanocomycin Intermediate S Aureus
• VRSA- Vancomycin resistant S. Aureus
• VRE- Vancomycin resistant entercoccus
• SSTI- Skin and Soft tissue infection
• CSSTI- Complicated SSTI

7. Newer Antibiotics in Use
• Cefepime- 4th Generation cefalosporin
• Aztreonam
• Linezolid
• Tigecycline
• Teicoplanin
• Levofloxacin/Moxifloxacin
• Imipenem/Meropenem

8. Cefepime
• Excellent aerobic Gram positive coverage including
pseudomonas aeruginosa and other bacteria
producing AmpC b-lactamases.
• Gram postive activity is similar to ceftriaxone.
• Indication-
– Emperic use in Febrile Neutropenia
– Resistant Gram positive and negative infections
Limited known effect in Meningitis
Side effects- Anaphylaxis, Interstitial nephritis, anemia and
leukopenia.

9. Aztreonam
β-Lactam (monobactam) antibiotic
Spectrum gram-negative aerobic bacteria, Enterobacteriaceae,
and Pseudomonas aeruginosa.
Useful in penicillin and cephalosporin allergies as no apparent
cross-reactivity occurs.
Cautions: Rash, thrombophlebitis, eosinophilia. Renally
eliminated.
Drug interaction: Probenecid.

10. Imipenem-cilastatin
• Injection. Carbapenem antibiotic with broad-spectrum activity
against gram-positive cocci and gram-negative bacilli, including P.
aeruginosa and anaerobes. No activity against Stenotrophomonas
maltophilia.
• Approved for use in Pediatric age group
• Cautions: β-Lactam safety profile (rash, eosinophilia), nausea,
seizures.
• Cilastatin possesses no antibacterial activity; reduces renal
imipenem metabolism. Primarily renally eliminated.
• Drug interaction: Possibly ganciclovir.

11. Meropenem
• Injection. Carbapenem antibiotic with broad-spectrum activity against
gram-positive cocci and gram-negative bacilli, including P. aeruginosa
and anaerobes. No activity against Stenotrophomonas maltophilia.
• Preferred carbapenem for treatment of CNS infections
• Cautions: β-Lactam safety profile; appears to possess less CNS
excitation than imipenem. 80% renal elimination.
• Drug interaction: Probenecid

12. Polymixin
• Polymyxins are antibiotics, with a general structure consisting of a
cyclic peptide with a long hydrophobic tail.
• They disrupt the structure of the bacterial cell membrane by
interacting with its phospholipids.
• They are produced by non-ribosomal peptide synthetase systems in
Gram-positive bacteria such as Paenibacillus polymyxa and are
selectively toxic for Gram-negative bacteria due to their specificity
for the lipopolysaccharide molecule that exists within many Gram-
negative outer membranes.
• The global problem of advancing antimicrobial resistance has
recently led to a renewed interest in their use.

13. Newer Antibiotics
• FDA Approved Antibiotics which are marketed
internationally
– Linezolid
– Daptomycin
– Tigecycline
– Dalfopristin-quinupristin
– Newer Fluroquinolones
– Newer Beta-Lactam Antibiotics
– Tetracycline
– Macrolides

14. Oxazolidinones
In clinical use: Linezolid In clinical trials: Radezolid, torezolid.
• Effective against Organisms-
– gram-positive bacteria including MRSA, VRE and Streptococcus pneumoniae.
– Mycobacterium tuberculosis and Nocardia.
Linezolid- 1st to be approved this millenium
• Indicated-
– VRE infections
– nosocomial and community-acquired pneumonia,
– skin and soft tissue infections.(SSTIs)
• bacteriostatic against drug-resistant organisms like MRSA and VRE. Inhibits bacterial
protein synthesis at an early stage and inhibits the formation of a functional initiation
complex.
• Resistance- Mutations in the peptidyl transferase centre of the rRNA
• Serious adverse effects - bone marrow suppression, peripheral and optic neuropathy,
lactic acidosis, and serotonin syndrome.

15. Clinical Outcomes of Linezolid vs Vancomycin in Methicillin-ResistantStaphylococcus
aureus Ventilator-Associated Pneumonia -Retrospective Analysis Jeannie D. Chan Et Al
• Background: Vancomycin has been the treatment standard for methicillin-resistantStaphylococcus
aureus (MRSA) infections, but clinical efficacy is limited.
Methods: Retrospective analysis of 113 participants with MRSA VAP confirmed by bronchoscopy who
have been initiated on therapy with either vancomycin or linezolid within 24 hours after
bronchoscopy and completed ≥7 days of therapy during their hospitalization from July 2003 to June
2007. The primary endpoints were hospital survival and clinical cure, defined as resolution of signs
and symptoms of VAP or microbiological eradication after completion of therapy along with clinical
pulmonary infection score (CPIS) ≤6 at day 7 of therapy.
• Results: At hospital discharge, 23/27 (85.2%) of linezolid and 72/86 (83.7%) of vancomycin
recipients had survived (P = .672). In comparison to linezolid recipients, the adjusted odds ratio (OR)
for survival was 0.72 (95% confidence interval [CI]: 0.16-3.27) with vancomycin therapy. Clinical cure
was achieved in 24/27 (88.9%) of linezolid and 63/86 (73.3%) of vancomycin recipients (P = .066).
• Compared to linezolid recipients, the adjusted OR for clinical cure was 0.24 (95% CI: 0.05-1.10) with
vancomycin therapy. Survival and clinical cure did not differ significantly between vancomycin
recipients with trough level ≥15 and <15 μg/mL, respectively.
• Conclusions: No survival benefit but a trend toward higher cure rate with linezolid therapy.
J Intensive Care MedNovember/December 2011 vol. 26no. 6 385-391

16. ZEPHyR study
• The ZEPHyR (Linezolid in the treatment of subjects with nosocomial pneumonia proven to be due to
methicillin-resistantStaphylococcus aureus) study was the largest ever conducted in this population.
• Investigators from 156 centers worldwide randomized 1,225 patients, of whom 448 patients had proven
MRSA nosocomial pneumonia (modified intent-totreat group); 339 patients also met key protocol criteria
at the end of study (per-protocol group) and were included in the primary analysis.
• In the per protocol group, 125 patients treated with linezolid (68.3%) and 140 (74.5%) treated with
vancomycin were ventilated at baseline
• Clinical success rates at the end of study were 57.6 percent (95/165) for patients treated with linezolid
compared with 46.6 percent (81/174) for patients treated with vancomycin in the per-protocol group, the
primary endpoint. These results demonstrated that linezolid achieved a statistically significantly higher
clinical success rate compared to vancomycin (95% CI for the difference in response rates: 0.5%, 21.6%; p
= 0.042).
• Overall mortality was 15.7% for linezolid and 17.0% for vancomycin.
• Thrombocytopenia (linezolid 1.3%, vancomycin 2.2%) and renal failure (linezolid 3.8%; vancomycin 7.2%)
occurred at relatively low rates.

17. Walkey et al combined 8 randomized trials including 1,641 people with MRSA pneumonia, and found
no significant differences between those treated with linezolid or vancomycin in survival,
resolution of clinical pneumonia, eradication from sputum of MRSA, or adverse events. Authors
dispute linezolid’s supposedly higher lung penetration, pointing out that that dogma evolved from
studies of healthy people; inflamed lungs seem to retain more vancomycin.
.CHEST 2011;139:1148-1155.
Linezolid versus Vancomycin in Treatment of Complicated Skin and Soft Tissue Infections John
Weigelt1, et al the Linezolid CSSTI Study Group , American Society for Microbiology,
doi: 10.1128/AAC.49.6.2260-2266.2005
• a randomized, open-label, comparator-controlled, multicenter, multinational study that included
patients with suspected or proven MRSA infections that involved substantial areas of skin or deeper
soft tissues, such as cellulitis, abscesses, infected ulcers, or burns (<10% of total body surface area).
• Patients were randomized (1:1) to receive linezolid (600 mg) every 12 h either intravenously (i.v.) or
orally or vancomycin (1 g) every 12 h i.v. ]
• Linezolid outcomes (124/140 patients or 88.6%) were superior to vancomycin outcomes (97/145
patients or 66.9%) at the TOC visit for patients with MRSA infections (P < 0.001).
• The results of this study demonstrate that linezolid therapy is well tolerated, equivalent to
vancomycin in treating CSSTIs, and superior to vancomycin in the treatment of CSSTIs due to
MRSA.

18. Linezolid versus vancomycin for the treatment of gram-positive bacterial
infections: meta-analysis of randomised controlled trials.
• Int J Antimicrob Agents. 2010 Jan;35(1):3-12. doi:10.1016/j.ijantimicag.2009.09.013. Epub 2009 Nov 8.
Beibei L, Yun C, Mengli C, Nan B, Xuhong Y, Rui W.
• Nine RCTs studying 2489 clinically assessed patients were included in the meta-
analysis. Overall, there was no difference between linezolid and vancomycin
regarding treatment success in clinically assessed patients [odds ratio (OR)=1.22,
95% confidence interval (CI) 0.99-1.50].
• Linezolid was more effective than vancomycin in patients with skin and soft-tissue
infections (OR=1.40, 95% CI 1.01-1.95). However, there was no difference in
treatment success for patients with bacteraemia (OR=0.88, 95% CI 0.49-1.58) or
pneumonia (OR=1.16, 95% CI 0.85-1.57).
• Linezolid was associated with better eradication rates in all microbiologically
assessed patients compared with vancomycin (OR=1.33, 95% CI 1.03-1.71).
• However, nephrotoxicity was recorded more commonly in patients receiving
vancomycin (OR=0.31, 95% CI 0.13-0.74).
In conclusion, linezolid is as effective as vancomycin in patients with gram-positive
infections. There is superior clinical and microbiological outcome with linezolid in
complicated skin and soft-tissue infections caused by Staphylococcus aureus.

19. Glycolipopeptides
• In clinical use: Daptomycin, telavancin Under clinical trials: Oritavancin.
Daptomycin- cyclic lipopeptide with a decanoyl side-chain
• Approved by the FDA in 2003 for the treatment of complicated SSTIs caused organisms-
– MSSA, MRSA, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus
dysgalactiae and Enterococcus faecalis (vancomycin-susceptible only).
– Rapid bactericidal activity against most gram-positive organisms including multiple-antibiotic
resistant strains.
• Shows promise in experimental models of endocarditis, meningitis, ventriculitis, and peritonitis,
and is currently approved for use in skin and soft-tissue infections. Ther Clin Risk Manag. 2006 June; 2(2):
169–174.Published online 2006 June.PMCID: PMC1661656A review of daptomycin for injection (Cubicin) in the treatment of
complicated skin and skin structure infections. Contraindicated in pneumonia.
• MOA- Acts by inserting its lipophilic tail in the bacterial cell membrane resulting in rapid
membrane depolarization and potassium ion efflux. This is followed by arrest of DNA, RNA and
protein synthesis, and finally cell death.
• Drug interactions could occur when daptomycin is used with statins and aminoglycosides.
• It causes reversible myopathy as one of its side effects.

20. Glycopeptides
Telavancin- approved in 2009 for CSSTIs caused by gram-positive bacteria
including MRSA strains.
In vitro activity against some vancomycin-resistant gram-positive organisms
has been observed.
• Dual mechanism of action –
– inhibits peptidoglycan chain formation through blockage of both,
transpeptidation and transglycosylation during cell wall formation.
– dissipates membrane potential of the bacterial cell membrane causing an
increase in permeability.
• Adverse effects-
– vomiting, paresthesias, dyspnea, microalbuminemia, taste disturbances and
thrombocytopenia.
– Renal function should be monitored before, during and after telavancin
therapy.
– Telavancin is not recommended in pregnancy.

21. Pleuromutilins
• In clinical use: Retapamulin In clinical trials: BC-3781.
Retapamulin
• first pleuromutilin that was approved in 2007 for topical use in the
treatment of uncomplicated superficial skin infections.
MOA-
inhibiting protein synthesis. Active against mupirocin-resistant strains.
• Retapamulin appears to be approximately 1000 times as potent as
mupirocin or fusidic acid against Streptococcus pyogenes.
• Effective against many common skin pathogens and has low potential for
development of bacterial resistance.
• Side effects - pruritus and allergic contact dermatitis.

22. Newer antibacterials belonging to
chemical classes in use before the
year 2000
• Newer antibacterials belonging to chemical
classes in use before the year 2000 are
described below

23. Streptogramins
• Newer streptogramins are: In clinical trials: NXL 103.
• The currently licensed agent- dalfopristin-quinupristin (Synercid), which is available in a
parenteral formulation.
• Spectrum - MRSA, CONS, penicillin-susceptible and penicillin-resistant S. pneumoniae,
and vancomycin-resistant E. faecium but not E. faecalis,VISA
• There is little information on dalfopristin-quinupristin and linezolid in treatment of CNS
infections, and neither agent is approved for pediatric meningitis.
• Indication-
– serious infection with VISA and VRE
– Serious infection with MRSA when Vancomycin is not tolerated
• Streptogramin antibiotic (quinupristin) active against vancomycin-resistant E. faecium
(VRE) and methicillin-resistant S. aureus (MRSA). Not active against E. faecalis.
• Adverse events: Pain, edema, or phlebitis at injection site, nausea, diarrhea,
arthalgia,myalgia.
• Drug interactions: potent inhibitor of CYP 3A4.

24. Quinolones
• The newer quinolones include: In clinical use: Gemifloxacin, besifloxacin
• Many of the new fluoroquinolones have anti-pseudomonal activity and additional anti-
MRSA activity.
Gemifloxacin
• Oral fluoroquinolone approved in 2003 for treatment of acute bacterial exacerbation of
chronic bronchitis and mild-to-moderate community-acquired pneumonia.
• shows enhanced activity against gram-positive bacteria( Strep, Staph) and atypical
pathogens ( Chlamydia pn, mycoplasma, legionella) but less against Pseudomonas than
ciprofolxacin. However, it has poor activity against methicillin-resistant strains.
• Anaerobic acivity +
• high affinity for DNA gyrase and topoisomerase IV. good activity against fluoroquinolone-
resistant strains including fluoroquinolone-resistant H. influenzae.
• High concentrations are achieved in the respiratory tract after oral administration, making it
an ideal drug for the treatment of respiratory tract infections.
No Ped Dosing available.
Besifloxacin – ophthalmic ointment
• Gatifloxacin has been banned due to the risk of severe hyperglycemia.
• Trovafloxacin has been withdrawn from the market due to risk for hepatotoxicity.
• NXL-101 was discontinued in trials due to prolongation of QT interval

25. Newer beta-lactam antibacterials
• The newer beta-lactam antibacterials include:
In clinical use
• Cephalosporins: Cefditoren pivoxil, ceftaroline
• Carbapenems: Ertapenem and doripenem. Biapenem is approved in some
European countries but not in the United States.

26. Newer beta-lactam antibacterials in clinical use
Cefditoren pivoxil
oral cephalosporin approved by the FDA for clinical use in 2001.
3rd generation oral cephalosporin with good activity against certain respiratory
tract pathogens
Spectrum- S. pneumoniae, H. influenzae and M. catarrhalis, including some β-
lactamase producing strains, Staphylococcus aureus (but not MRSA strains)
and Streptococcus pyogenes (penicillin-susceptible strains only).
Used in the treatment of mild-to-moderate acute bacterial exacerbation of
chronic bronchitis and community-acquired pneumonia, pharyngitis or
tonsillitis, and uncomplicated skin and skin-structure infections.
Pediatric use- approved

27. Beta Lactam Antibiotics
• Ceftaroline and ceftobiprole- ‘fifth-generation’ cephalosporin.
Ceftaroline-
• Newest cephalosporin with anti-MRSA activity that obtained FDA
approval in October 2010.
• Indication-
– acute bacterial skin and skin-structure infections, and
– community-acquired bacterial pneumonia.
• Spectrum-
– MSSA as well as MRSA, Strep. Pyogenes, agalactiae, and pneumoniae, hVISA
and VRSA
– Gram-negative -ceftazidime-susceptible E. coli and Kleb. pneumoniae, and β-
lactamase-positive and negative Haemophilus influenzae,
• Synergistic when combined with amikacin, tazobactam, meropenem and
aztreonam.
• the low potential for resistance development and the favorable safety and
tolerability profile in clinical trials, Available IV

28. Carbapenems
widest spectrum of antibacterial activity of all the beta-lactams
excellent coverage- Gram - and Gram + aerobic and anaerobic bacteria.
bactericidal agents that bind to the PBPs inhibiting the bacterial cell wall synthesis.
Less resistance than other beta-lactams because of their stability to hydrolysis by
many extended-spectrum chromosomal and plasmid-mediated beta-lactamases,
including AmpC and extended-spectrum beta-lactamases (ESBLs).

29. CARBAPENEMS-
Ertapenem
1-β-methyl carbapenem approved for use by the FDA in the year 2001.
Spectrum- gram-positive and negative aerobic as well as anaerobic
bacteria excluding the nonfermenters, MRSA and drug-resistant
enterococci. E
Effective against most resistant enterobacteriaceae producing ESBLs
and/or AmpC-type β-lactamases. limited in vitro activity against P.
aeruginosa and Acinetobacter species, not suitable for the empiric
treatment of serious infections acquired nosocomially.
Recommended for prophylaxis of surgical-site infection following
elective colorectal surgery. Unlike imipenem, ertapenem does not
require co-administration with cilastin.

30. Doripenem
• Doripenem was approved for use by the FDA in 2007. Its spectrum is more similar
to that of meropenem and imipenem than of ertapenem. Thus, it is effective
against gram-positive and negative aerobes and anaerobes including Pseudomonas
aeruginosa, Acinetobacter species, but not MRSA, VRE and other strains resistant
to imipenem and meropenem. It is effective against β-lactamase producing strains
of enterobacteriaceae
• Doripenem is approved for the treatment of intra-abdominal infections and
complicated urinary tract infections including pyelonephritis.
• Dosage adjustment is required in renal failure patients.

31. Beta Lactamase Inhibitor
• β-lactamase inhibitors In β-lactam agent/β-lactamase inhibitor combinations, the latter potentiates the action of the former by
protecting it from enzymatic hydrolysis.
• Currently used β-lactam/β-lactamase inhibitor compounds are highly active against class A and various ESBLs, but with poor
activity against class C and class D enzymes.
• Their main advantage over the older available β-lactamase inhibitors is conferred by the ability to inhibit class C and D
enzymes. Thus, MIC of various currently used β-lactams, such as piperacillin or ceftazidime, is decreased when administered
together with novel β-lactam inhibitors, these antibiotics become active against ESBL-producing strains.
• Moreover, used combined with carbapenems, makes the latter active against MBL-producing strains.
• Avibactam (also known as NXL104) is a β-lactamase inhibitor that has no antibacterial activity, but has interesting property to
inhibit beta-lactamases. Currently it is in clinical development combined with both ceftazidime Bassetti et al.and ceftaroline. It
displays a broad-spectrum inhibitory profile against enzymes belonging to classes A and C β-lactamases (including AmpCs,
ESBLs, and KPC) [52], on the other side, in combination with aztreonam it offers a potential option against bacteria producing
NDM-1 [53]. There are several on-going studies in phase III, assessing the efficacy in association with ceftazidime in the
treatment of cIAI, HAP and cUTI [54,55]. mMK-7655 is a novel beta-lactamase inhibitor under clinical development. It displays
good in vitro activity against class A and class C carbapenemases, especially when combined with imipenem/cilastatin.
Currently the drug is in phase II clinical development trial for the treatment of cIAI and cUTI [56].
• ME1071 (CP3242), a class-B inhibitor, maleic acid derivative,is a novel specific inhibitor for metallo-β-lactamases (MBL). It
reduces the MICs of carbapenems for bacteria with NDM-1 enzyme. It can potentiate the activity of carbapenems (expecially
biapenem) and ceftazidime against MBL-producing strains of P. aeruginosaand other Gram-negative bacteria, as E. coli, Serratia
marcescens, A. Baumanii and K. pneumoniae. It shows less activity

32. Newer macrolides and ketolides
• Newer macrolides and ketolides include:
• In clinical use: Fidaxomicin, telithromycin
• Ketolides are derivatives of macrolides with replacement of L-cladinose on the
macrolide ring with a 3-keto group.
Newer macrolides and ketolides approved for use
Fidaxomicin
• Fidaxomicin is probably the latest antibacterial approved for use in May 2011.
• Indicated- Clostridium difficile-associated diarrhoea. Rates of recurrence for some
strains of Clostridium difficile have also been found to be lower with fidaxomicin as
compared to vancomycin in clinical studies.
• Preferred drug in cases of recurrence.
• MOA- Bactericidal- inhibiting bacterial RNA polymerase.
• It is minimally or not absorbed following oral administration, thus systemic side
effects are reduced.
• It does not affect the normal flora of the lower gastrointestinal tract since it does not
show any activity against gram-negative organisms.
Telithromycin – withdrawn for severe side effects

33. Newer tetracycline-related antibacterials
• Newer antibacterials related to tetracyclines include:
• In clinical use: Tigecycline In clinical trials: PTK-0796.
Tigecycline
• Glycylcycline - structural derivative of minocycline. Approved for use in the year
2005 for complicated skin and soft-tissue infections, community-acquired bacterial
pneumonia and complicated intra-abdominal infections. Its efficacy against gram-
negative as well as positive organisms makes it a useful drug in mixed infections.
• Tigecycline also shows potent activity against a number of resistant organisms.
• MOA- binds avidly to the ribosome and does not undergo active efflux easily in
gram-positive organisms. However, it is susceptible to efflux from organisms
like Pseudomonas aeruginosa, Proteus spp., Providencia spp., and Morganella spp.,
which makes these organisms inherently drug resistant to tigecycline.
• MIC90 values for A. baumannii of 1-2 mg/L have been reported to be the lowest
among all antimicrobials including carbapenems.
• Dosage reduction may be required in severe hepatic impairment. It has excellent
tissue penetration, thus supporting its use in deep tissue infections.
• Gastrointestinal adverse effects like nausea, vomiting, diarrhoea and heartburn
are commonly observed with tigecycline. It is contraindicated in pregnancy and
children below 8 years of age.

34. Newer trimethoprim-related Drug
• recently been accepted as New Drug Application by the FDA for the treatment of
complicated skin and soft-tissue infections.
• Iclaprim, a dihydrofolate reductase inhibitor, is being developed as a single agent,
though it does show synergistic effect when administered with some
sulfonamides.
• Spectrum- S. aureus and S. pneumoniae, including several resistant strains. Its
effectiveness against H. influenzae, Moraxella catarrhalis and Legionella
pneumophila may also make it useful in respiratory tract infections. It is being
developed as an intravenous as well as oral formulation.
• Iclaprim has undergone Phase III trials

35. Antibiotics in Pipeline
Oxazolidinones-
Radezolid-.
Torezolid-
useful in persistent intracellular infections
More potent,Bactericidal and active
against linezolid-resistant strains of S.
aureus in vitro. CSSTIs with good efficacy
and an acceptable side effect profile.
completed phase II clinical
trials
A second-generation oral
oxazolidinone
Pluromutilin
BC-3781
likely to be used for the treatment of
serious skin infections and pneumonia. It
appears similar in efficacy to vancomycin
with a good safety and tolerability profile.
first pleuromutilin
antibacterial for systemic
use.
completed Phase II trials
Quinolones
Nemonoxacin, finafloxacin,
JNJ-Q2, delafloxacin,
prulifloxacin, zabofloxacin
In clinical trials

36. Antibiotics in Pipeline
Streptogramin
NXL-103
novel, orally administered
effective against gram-positive cocci
including MRSA, MRSE and VRE, gram-
negative rods and anaerobes and has the
potential to be used in infections like CAP,
community-acquired or nosocomial MRSA
and VRE infections, and CSSTIs.
Phase II trials.
contains linopristin and
flopristin in a 30:70 ratio
shown to be up to 4 times
more potent than
quinupristin/dalfopristin
in in vitro tests.
Glycolipodepepsipeptide
Ramoplanin-Unlike
glycopeptides, it does not
complex with the D-Ala-D-Ala
sequence of cell wall
precursors to inhibit cell wall
synthesis.
Undergoing for use in Clostridium-
difficile associated diarrhoea.
Ramoplanin inhibits cell wall synthesis by
inhibiting peptidoglycan formation.
phase III clinical trials
Effective only when
administered orally and is
not absorbed systemically,
it is useful in local
gastrointestinal infections.

37. Antibiotics in Pipeline
Nemonoxacin nonfluorinated quinolone
community-acquired pneumonia and
diabetic foot infections.
good activity against a variety of gram-
positive and negative organisms including
MRSA, VRE and other multi-drug-resistant
organisms.
completed phase II clinical
trials
Finafloxacin proven activity against MRSA, VRE and
other drug-resistant strains as well as
anaerobes.
Oral and IV formulations of finafloxacin are
undergoing
High tissue levels are achieved even in
acidic environments of pus, urine and
secretions from infected tissues. Currently,
it is being tested for urinary tract
infections and H pylori infections.
phase II clinical trials.
Its once-a-day
administration makes it an
attractive drug.
safe without prolongation
of QT interval and other
serious side effects
associated with
fluoroquinolones.
Delafloxacin- new
fluoroquinolone
good activity against gram-positive,
including MRSA strains, gram-negative
organisms and anaerobes including
resistant strains.
CSSTIs, CAP and bronchitis.
In clinical trials

38. Antibiotics in Pipeline
Cephalosporin:
Ceftobiprole- IV fourth-
generation cephalosporin
being developed for CAP, SSTIs due to MRSA,
and nosocomial pneumonia due to suspected
or proven MRSA, including VAP.
limited activity against anaerobes and is not
effective against extended spectrum β-
lactamase, serine carbapenemases and
metallo-β-lactamases producing species
facilitates a conformational change in
penicillin-binding protein PBP2a, allowing the
formation of a stable acyl-enzyme complex.
approved for use in some
countries
Carbapenems:
Razupenem- novel β-
methyl carbapenem
ME 1036
complicated skin and soft-tissue infections.
active against MRSA and VRE including
Enterococcus faecalis but not Enterococcus
faecium. some activity against
Enterobacteriaceae.
It shows in vitro potency against resistant
gram-positive organisms, including MRSA and
VRE, and ESBL-producing E. coli and K.
pneumoniae but is not effective against P.
aeruginosa.
completed Phase II clinical
trials
Others
Sulopenem

39. Antibiotics in Pipeline
Macrolides and Ketolides
EDP-420
Cethromycin
Solithromycin
All being tried in Pneumonia
EDP-420 has some activity against
myobacterium avium
Different stages of Trial
Aminoglycoside
Plazomicin Inhibits bacterial protein synthesis.
This new intravenous aminoglycoside
demonstrates activity against Gram-positive
and Gramnegative pathogens
In vitro synergism with daptomycin and
ceftobiprole against MRSA, hVISA and VISA
and with doripenem, imipenem, piperacillin/
tazobactam and cefepime against P.
aeruginosa
Phase II study in patients
with cUTI and acute
pyelonephritis,
including cases with
concurrent bacteremia,
compared plazomicin with
levofloxacin

40. Antibiotics in Pipeline
CB-182,804 is a novel
polymyxin analogue good in vitro activity against MDR Gram-
negative bacteria, such as A. baumannii,
E. coli, K. pneumoniae and P. aeruginosa.
high activity against colistin-susceptible
and -resistant isolates.
Currently the.
Phase I clinical stage

41. Take home message
Although the Bacterial resistance is developing rapidly , newer antibiotics
in pipeline provides us some hope.
MRSA,VRSA,VRE, ESBL, Pseudomonas are major resistant organisms
Against which most new antibiotics are targeted.
Rationale use of the antibiotics is necessary because erratic use in past
Has led to rapid and extensive drug resistance
Few are marketed in Nepal
Need of Newer antibiotics in Nepal market