Newer antibiotics and uses

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The newer antibiotics added to Our Arsenal against resistant bacteria. Know about the upcoming antibiotics and newer antibiotics in use.

The newer antibiotics added to Our Arsenal against resistant bacteria. Know about the upcoming antibiotics and newer antibiotics in use.

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  • It is inactivated by surfactant and is therefore cDalbavancin, a glycolipopeptide that requires only once-a-week dosing,[5] has been withdrawn from the market following feedback from regulatory authorities. Development of friulimicin, a lipopeptide was discontinued after a Phase I intravenous escalating-dose trial indicated that the pharmacokinetic profile of the drug was unfavourable.[2]
  • hetero-resistant vancomycin-intermidiate S. aureus

Transcript

  • 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