Int J App Pharm, Vol 10, Issue 3, 2018, 13-18Review Article
REVIEW ON CLINICALLY DEVELOPING ANTIBIOTICS
NIRANJANA E. S.1, SAMBATH KUMAR R.2*, SUDHA M.3, VENKATESWARAMURTHY N.1
1Department of Pharmacy Practice, 2Department of Pharmaceutics, 3Department of Pharmacology, J. K. K. Nattraja College of Pharmacy, Kumarapalayam 638183
Email: sambathkumar.r@jkkn.org
Received: 19 Sep 2017, Revised and Accepted: 13 Apr 2018
ABSTRACT
The world is running out of antibiotics. Between 1940 and 1962, more than 20 new classes of antibiotics were marketed. Since then, only two new classes of antibiotics were marketed. Now, not enough analogues are reaching the market to stem the tide of antibiotic resistance, particularly among gram-negative bacteria which indicates the need of novel antibiotics for their effective action. This review describes those antibiotics in late-stage clinical development. Most of them belong to existing antibiotic classes and a few with a narrow spectrum of activity are novel compounds directed against novel targets. The reasons for some of the past failures to find new molecules and a path forward to help attract investments to fund the discovery of new antibiotics are described.
Keywords: Antibiotics, Clinical development, Narrow spectrum
© 2018 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijap.2018v10i3.22668
INTRODUCTION
The antibiotics are the cornerstones of recent medicine after the entry of penicillin, which came into widespread use in the beginning of the 1940s. [1] By 1950s, multiple numbers of newer classes of antibiotics came into the scene, over the next twenty years. [2] Nowadays it is difficult to treat and do certain medical procedures which are extensively used, like chemotherapy, organ transplants, joint operations or the provision of care for premature babies without the antibiotics [1]. Moreover, they can control both morbidity and mortality rate in humans and animals. [3] To brief outing, they have become the lifesaving treatment for all types of infections in humans as well as animals. The timeline of new class antibiotics has been given in table 1.
Table 1: Time line of antibiotics
| Year introduced | Class of drug |
1935 1941 1944 1945 1949 1950 1952 1956 1957 1959 1962 1968 2000 2003 |
Sulphonamides Penicillins Aminoglycosides Cephalosporins Chloramphenicol Tetracyclines Macrolides/lincosamides/streptogramins Glycopeptides Rifamycins Nitroimidazoles Quinolones Trimethoprim Oxazolidinones Lipopeptides |
Now, however, two developments are resulting in more and more difficult to treat the bacterial infections with the antibiotics successfully, including the increasing number of antibiotic-resistant pathogens and the second one is that the number of new antibiotics developed since the 1970s has decreased [4]. It was estimated that infections that can be treated completely are also becoming more complicated to treat, increasing costs of healthcare facilities, and patient mortality is increasing with costs to the society. The antibiotic effectiveness has to decrease now and many of the microorganisms are resistant to multiple antibiotics [5]. The issue of antibiotic resistance, though not new, has amplified in the previous 10 to 15 y and creates a serious threat to the treatment of infections. Certain new investigational studies were reported that, among all the multidrug-resistant pathogens like S. aureus and P. aeruginosa, Acinetobacter species are the major infective organism which can cause even life-threatening resistant infections. The improper intake of antibiotic dosage or lack of sensitive antibiotic agents to fight against these types of organisms may be the reason for the occurrence of such infections [6].
Despite this increase in the multidrug-resistant pathogens, the development of antibacterial agents is declining, [7] that is, there are not enough antibiotics for treating such infections [4]. This antibiotic deficit will become more and more problematic in the years to come.
As per World Health Organization (WHO), the antibiotic resistance is one among the serious hazard to human health and the consequences of antibiotic-resistant bacterial infections are greater than ever [4]. So, new antibiotics are critically needed to alleviate the problems associated with this antibiotic resistance [8, 9]. The Infectious Diseases Society of America (IDSA, 2010) estimated that at least another 10 antibiotics, which are active against these superbugs, are required to enter the market within ensuing ten years [10]. It ought to be noted that antibiotics, which were already in market use are complex natural products with multiple binding sites on the target, making it less likely for resistance selection. Moreover, the prevalence of treatment difficulty for both resistant and multi-resistant nosocomial organisms are greatly rising, both for Gram-negative and Gram-positive bacteria among this; gram-negative organisms are producing a greater threat [11].
Thus, the demand for new antibiotics is critical for some gram-negative microbes as compared to gram-positive microbes since the new molecules or compounds will produce action in new pathways to eradicate such microbes [12]. Generally, small proteins are the greatest source of new antibiotics called antimicrobial peptides (AMPs) and many of these AMPs are derived from natural molecules [13]. The current study reviews all the current articles on clinically developing antibiotics and describes their needs and scope in the market.
Search criteria
Articles related to new antibiotics and their developments were reviewed for the study, most of them were from Pubmed databases. Articles between the years of 2000 and 2017 were selected for reviewing and the points were extracted. Primary resources were given the first preference for reviewing.
Approval and development of antibiotics from the ‘Golden Era’
The response to the entry of any new antibiotic has lead to the development of resistant bacterial variants so, new antibiotic compounds should be needed constantly to alleviate the associated problems. During the "golden era" of antibiotic evolution, that is, in the years of 1940s to 1970s, new antibiotics with new actions were incessantly developed, which made it possible to manage the threat of gradually rising resistant strains. [8] The European Medicines Agency (EMA) and the American Food and Drug Administration (FDA) were the two agencies responsible for making the approval decisions for new antibiotics. The new antibiotics, which are approved in the year of 2000 and 2011, are listed below (table 2).
Table 2: Status of antibiotics approved by the FDA and the EMA between 2000 and 2011
| Substance | Class | Rejected by FDA | Approved by FDA | Approved by EMA |
| Linezolid | Oxazolidinones | 2000 | ||
| Ertapenem | Carbapenems | 2001 | 2002 | |
| Cefditoren | Cephalosporines | 2001 | ||
| Gemifloxacin | Fluoroquinolones | 2003 | ||
| Daptomycin | Lipopeptides | 2003 | 2006 | |
| Telithromycin | Macrolides | 2004 | ||
| Tigecycline | Glycylcyclines | 2005 | 2006 | |
| Faropenem | Penems | 2006 | ||
| Retapamulin | Pleuromutilins | 2007 | 2008 | |
| Dalbavancin | Glycopeptides | 2007 | ||
| Doripenem | Carbapenems | 2007 | 2008 | |
| Oritavancin | Glycopeptides | 2008 | ||
| Cethromycin | Macrolides | 2009 | ||
| Cethromycin | Macrolides | 2009 | ||
| Iclaprim | Trimethoprims | 2009 | ||
| Besifloxacin | Fluoroquinolones | 2009 | ||
| Telavancin | Glycopeptides | 2009 | 2011 | |
| Ceftobiprole | Cephalosporines | 2009 | ||
| Fidaxomicin | Lipiarmycins | 2011 | 2011 | |
| Colistimethate sodium | Colistin | 2012 | ||
| Ceftaroline | Cephalosporines | 2010 | 2012 |
However, the world’s capacity for antibiotic discovery is already reducing the rate of emergence of bacterial resistance, and which indicates the necessity of another new class of antibiotics to be introduced in the market (Figure1). Fig. 1 showed a line drawing of total number of newer classes of antibiotics that entered to the market in the years of 1940s and 1960s, the two new classes since 2000, and further 20-40 new classes were required to support medicine in the future years from now [6].
Fig. 1: Number of antibiotics in the market and the predictions of new antibiotics needed for the future
Novel antibiotics in recent years
The majority of new antibiotic substances is in the early phase of development is, phase 1 clinical trials [4]. The clinical trials for new antibiotics are believed to be cover disease indications even if it is the infection caused by more than one bacterial species [14]. The research updates showed that only two new classes of antibiotics were marketed in last 10 y and it may be due to the lack of development and almost all the pharmaceutical companies were concentrating only on analogue development which may be due to the high toxicity risks associated with the new classes [15]. At present, the environment has changed a little positively, and those who observing preclinical and clinical development strategies and activities have a reason to be more optimistic [11].
Several compounds have been developed in various antibiotic classes which are against resistant organisms in the whole spectrum of multidrug-resistant (MDR) bacteria (fig. 2) [11].
Fig. 2: New antibiotic compounds acting against resistant organisms
Source Reference: https:/www.google.co.in.novelantibiotics diagram [16]
Since most of the infections can be cured without antibiotic therapy, thus, new antibiotic approval is generally limited to complicated or more serious infections. The Infectious Diseases Society of America (IDSA) emphasizes that selecting the optimal drug regimen; dose, duration, and route of administration are a very important part in the stewardship practice. Furthermore, stewardship seeks to diminish the toxicity and other adverse events and also to lessen the costs of healthcare infections [16].
It is not easy to estimate the numbers of drugs in preclinical development, as most of them are not published or marketed [17]. Still, there are no antibiotics against the major gram-negative microorganisms such as K. pneumoniae, P. aeruginosa and A. baumanii in Phase II b and III and also the number of compounds (analogs of existing markets antibiotics) against these pathogenic organisms in earlier stages of development are also lessened. Since there are no new classes of antibiotics in the final phases of drug development, the new class antibiotics will not be introduced in the market in the short term [10, 18]. In the longer term, during the next 20 y, the probability of inventing twenty new antibiotic classes like many broad-spectrum antibiotics, as similar in 1940-1960s, looks to be remote, especially for multi-drug-resistant gram-negative microorganisms.
Novel compounds against microorganisms which are under clinical development
• Compounds against Gram-positive bacteria
Novel long-acting lipoglycopeptides-oritavancin and dalbavancin
Acute bacterial skin and skin structure infections (ABSSIs) are considered as the major bacterial infection and the frequent indications for antibacterial therapy, which are usually induced by Gram-positive bacteria like MRSA (Methicillin-resistant Staphylococcus aureus). With the introduction of the newer lipoglycopeptides with an extended elimination half-life, ABSSSI therapy may become more convenient. Oritavancin acts by inhibiting transglycosylation (like vancomycin), transpeptidation (like beta-lactams), and disruption of cell membrane integrity (like telavancin) [19] and results in quick bactericidal activity. It has a long elimination half-life of>300 h [20] and showed a strong bactericidal activity in a dose of 1200 mg in the in vitro PK/PD model [21].
Dalbavancin is another semisynthetic lipoglycopeptide which has been estimated for skin and soft tissue/skin structure infections, [22, 23] and also for catheter-associated bloodstream infections. Its half-life is about two weeks [24] also allowed for prolonged dosing intervals. Dalbavancin had a favorable safety profile with fewer adverse effects. It is estimated that the usage of dalbavancin was joined up with a significantly lower mortality (0.2 vs. 1.1 %). Finally, this has proceeded to the FDA approval of dalbavancin for ABSSSI caused by S. Aureus and S. pyogenes in May 2014.
Drugs to destroy gram-negative bacteria and broad-spectrum antibiotics
BAL30072
BAL30072 is a monosulfactam antibiotic, have an action against carbapenem-resistant Enterobacteriaceae and non-ferments [25]. It is chemically related to aztreonam and coming under the class of beta-lactam antibiotic and inhibiting the cell wall synthesis of bacteria. Certain in vitro studies has shown that the combination of BAL30072 with BAL29880 or clavulanate can result in susceptibility rates of more than 90%. A study conducted in Thailand, with its laboratory strains (1026b, 1710b) and several strains which are isolated, it was observed that more than 93% of the isolates were susceptible to BAL30072 with minimal inhibitory concentrations (MICs) between 0.004-0.016 μg/ml [26]. BAL30072 showed high activity through a MIC 90 of 0.016 μg/ml as compared to ceftazidime, meropenem, and imipenem.
Ceftolozane
Ceftolozane with tazobactam is presently undergoing certain investigational studies for testing its action in complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs) and ventilator-associated pneumonia (VAP). It is a new cephalosporin which is structurally similar to ceftazidime, which active against Pseudomonas and also against bacteria-producing beta-lactamases such as TEM-1. [11] Ceftolozanealone cannot destoy or kill the bacteria-producing ESBL and carbapenemases. However, along with tazobactam, it can destroy most of the bacteria-producing ESBL and some anaerobes. The FDA approved ceftolozane/ tazobactam to treat adultscIAI and cUTI in December 2014 [27].
Delafloxacin (fluoroquinolone)
Delafloxacin is a fluoroquinolone and its efficacy is undergoing through various investigational studies. As compared with others, it has a substituent on the seventh position of the quinoline ring system which is not protonatable and causes a pKa shift. Generally fluoroquinolones are zwitterionic except delafloxacin and as a result, they are neutrally charged only at a physiological pH. The neutral charge is essential for membrane penetration. Delafloxacin permeates the membranes at lower pH as seen in the inflamed tissue [28, 29]. Generally, the pH levels are mildly acidic (about 5.5-6) in the inflammatory tissue of soft tissue infections, abdominal infections, or urinary tract infections, under these conditions, e. g., 90% of moxifloxacin is in a cationic state, so it cannot permeate the bacterial membranes. In contrast, delafloxacin is neutral at this pH and thereby leads to high cellular uptake [28].
Novel beta-lactamase inhibitors
The beta-lactamase inhibitors which are available for the clinical application includes sulbactam, clavulanate, tazobactam, etc. Recently, these beta-lactamases increases the resistance particularly to Gram-negative bacillieg. oxacillinasescephalosporinases and the metallo-beta-lactamases. Novel beta-lactamase inhibitors (e. g., diazabicyclooctane-related substances) are also able to inhibit these enzymes to a different extent. They, therefore, contribute substantially to meet the increasing need for new drugs against ESBL or Klebsiella pneumonia carbapenemases (KPCs)-producing bacilli [11].
Antibiotics currently under clinical development
SinceMarch 2017, about 41 novel antibiotics have been found to be under clinical investigation in the U. S. market for the management of potential bacterial infections. The achievement rate for such clinical drug development is low; the various study data showed that, generally, only 1 in 5 infectious disease products are entering into phase 1 clinical trial (human testing) [30]. The present antibiotic pipeline, on the basis of currently available information, is given in table 3. It will be revised in a periodic manner.
Table 3: List of compounds which are under clinical development
| Drug name | Company | Drug class | Target | Expected activity against resistantGram-negativeESKAPE pathogens | Expected activity against a CDCurgent threat pathogen | Potential Indications |
Baxdela(delafloxacin) Meropenem+Vaborbactam CRS3123 |
Melinta Therapeutics Inc. Rempex Phar maceuticalsInc Crestone Inc. |
Fluoroquinolone β-lactam (carbapenem)+β-lactamase inhibitor(cyclic boronate) Diaryldiamine |
Bacterial type IITopoisomerase PBP; β-lactamase MethionylTrnasynthetase [17] |
Possibl No |
Possibly Yes Yes |
ABSSIs, cUTI, Community-acquired pneumonia (CAP) [6] cUTI, cIAIs, Hospital-acquired bacterial pneumonia/ventilator associated bacterial pneumonia,Febrile neutropenia, Bacteremia.[6] C. difficileinfections |
| ETX2514SUL10 | Entasis Therapeutics Inc. | β-lactam (sulbactam)+β-lactamase inhibitor(diazabicyclooctane) | PBP; β-lactamase | Yes | No | Bacterial infections (caused byAcinetobacterbaumannii) [6] |
| GSK-334283010 | GlaxoSmithKlinePLC (Shionogilicensee) | β-lactam (cephalosporin) | PBP | Possibly | Possibly | Bacterial infections |
| KBP-7072 | KBPBioSciencesPharmaceuticalTechnical Co. Ltd. | Tetracycline | 30S subunit ofbacterial ribosome | Possibly | No | CAP [6] |
| LCB01-037110 | LegoChemBiosciences Inc. | Oxazolidinone | 50S subunit ofbacterial ribosome | No | No | Bacterial infections |
| MCB3837 | Morphochem AG | Oxazolidinone-quinolonehybrid | 50S subunit of bacterial ribosome; bacterial type IItopoisomerase | No | Yes | C. difficile infections[6] |
| MGB-BP-310 | MGBBiopharmaLtd. | Distamycin [16] | DNA minor groove | No | Yes | C. difficile-associated diarrhea |
| Nacubactam (OP0595/RG6080) | Meiji Seika PharmaCo. Ltd./FedoraPharmaceuticalsInc. (Rochelicensee) | β-lactamase inhibitor(diazabicyclooctane) | β-lactamase, PBP2 | Possibly | Possibly | Bacterial infections |
| SPR74 | Spero Therapeutics | Polymyxin | Cell membrane | Possibly | Possibly | Bacterial infections |
| TD-1607 | TheravanceBiopharma Inc. | Glycopeptide-β-lactam(cephalosporin) hybrid | PG chainelongation; PBP | No | No | ABSSIs, hospital-acquired pneumonia/ventilator-associated bacterial pneumonia, bacteremia. [6] |
| TP-271 | TetraphasePharmaceuticals inc | Tetracycline | 30S subunit ofbacterial ribosome | Possibly | Possibly | Community-acquired bacterial pneumonia |
| TP-60766 | TetraphasePharmaceuticals Inc | Tetracycline | 30S subunit ofbacterial ribosome | Possibly | Possibly | Bacterial infections |
| WCK 2349 | Wockhardt Ltd. | Fluoroquinolone (WCK771 pro-drug) | Bacterial type IItopoisomerase | No | No | Hospital-acquired bacterial pneumonia [6] |
| WCK 771 | Wockhardt Ltd. | Fluoroquinolone | Bacterial type IItopoisomerase | No | No | Hospital-acquired bacterial pneumonia [6] |
| Cefepime+Zidebactam(WCK 5222) | Wockhardt Ltd. | β-lactam (cephalosporin)+β-lactamase inhibitor(diazabicyclooctane) | PBP; β-lactamase | Yes | Possibly | cUTIs,hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia[6] |
| Aztreonam+Avibactam [7,10](ATM-AVI) | Pfizer Inc./AllerganPLC | β-lactam (monobactam)+β-lactamase inhibitor(diazabicyclooctane) | PBP; β-lactamase | Yes | Yes | cIAIs |
| Brilacidin | Cellceutix Corp. | Defensin mimetic16 | Cell membrane | No | No | ABSSIs |
| CG400549 | CrystalGenomicsInc. | Benzyl pyridinone | Fab1 inhibitor | No | No | ABSSIs, osteomyelitis [6] |
| Afabicin(Debio 1450) | DebiopharmInternational SA | Benzofurannaphthyridine | Fab1 inhibitor | No | No | ABSSIs and osteomyelitis (Staphylococcus-specific) |
| Finafloxacin | MerLionPharmaceuticalsPvt Ltd. | Fluoroquinolone | Bacterial type II topoisomerase | Yes | Possibly | cUTIs, acute pyelonephritis, cIAIs, ABSSIs |
| Gepotidacin(GSK2140944)15 | GlaxoSmithKlinePLC | Triazaacenaphthylene[16] | Bacterial type II topoisomerase(novel A subunitsite) [17] |
No | Yes | cUTIs, uncomplicatedUTI, ABSSIs uncomplicated urogenital gonorrhoeaand CAP [6] |
| MRX-I 14 | - | - | 50S subunit of bacterial ribosome | No | No | ABSSIs |
| Nafithromycin (WCK 4873) | Wockhardt Ltd. | Macrolide | 50S subunit of bacterial ribosome | No | No | CAP |
| Nemonoxacin | TaiGenBiotechnology Co. Ltd. | Quinolone | Bacterial type IItopoisomerase | No | No | CAP, diabetic foot infection, ABSSIs |
| Murepavadin (POL7080) | Polyphor Ltd. | Antimicrobial peptide mimetic | Targeting Pseudomonas LPS-assembly protein (OstA; LptD; Imp) | Yes (Pseudomonas) | No | Ventilator-associated bacterial pneumonia (caused by Pseudomonas aeruginosa), lower respiratory tract infection, Bronchiectasis |
| Ramoplanin | NanotherapeuticsInc. | Lipodepsipeptide | Lipid I,II | No | Yes | C. difficile infection[6] |
| Ridinilazole(SMT 19969) | SummitTherapeutics Inc. | Bis-benzimidazole[1] | Unknown | No | Yes | C. difficile infection [26] |
| Zoliflodacin(ETX0914) | EntasisTherapeutics Inc. | Spiropyrimidenetrione[16] | Bacterial type IItopoisomerase(GyrB) | No | Yes | Uncomplicated gonorrhea |
| Cadazolid | ActelionPharmaceuticalsLtd. | Oxazolidinone-quinolonehybrid | 50S subunit of bacterial ribosome; bacterial type Iitopoisomerase | No | Yes | C. difficile infection |
| Cefiderocol (S-649266)30 | Shionogi and Co. Ltd. | Siderophore-β-lactam(cephalosporin) | PBP | Yes | Yes | cUTI, carbapenem-resistant Gram-negative bacterial infections |
| Eravacycline | TetraphasePharmaceuticalsInc. | Tetracycline | 30S subunit of bacterial ribosome | Yes | Yes | cIAIs, cUTI |
| Iclaprim | Motif Bio PLC | 2,4 diaminopyrimidine | Dihydrofolatereductase | No | No | ABSSIs, hospital-acquired bacterial pneumonia |
| Imipenem/cilastatin+relebactam (MK-7655) | Merck and Co. Inc. | β-lactam (carbapenem)+β-lactamase inhibitor(diazabicyclooctane) | PBP; β-lactamase | Yes | Yes | cUTI,Acutepyelonephritis, cIAIs,hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia |
| Lefamulin (BC-3781) | NabrivavTherapeutics AG | Pleuromutilin[16] | 50S subunit ofbacterial ribosome | No | No | ABSSIs,CAP, hospital-acquired bacterial pneumonia/ventilator-associatedbacterial pneumonia, Osteomyelitis, prosthetic jointinfections [6] |
| Omadacycline | ParatekPharmaceuticalsInc. | Tetracycline | 30S subunit of bacterial ribosome | Yes | Possibly | CAP, ABSSIs |
CONCLUSION
There are many promising antibiotic compounds which are currently under clinical development which will be open up the possibilities for treating various life-threatening infections, but among them very few are reaching the stage of human testing. The resistance mechanisms are the main problem associated with the antibiotic therapy, but this will not stop with the entry of the new drugs into the market. Therefore, the race must continue, and drugs with new actions need to be investigated and tested for human use. The requirements should include that, the product is within the scope of combination regimes, should be made possible as this could help to delay the development of resistance.
AUTHORS CONTRIBUTIONS
All the author have contributed equally
CONFLICT OF INTERESTS
Declared none
REFERENCES
White AR. Effective antibacterials: at what cost? The economics of antibacterial resistance and its control. J Antimicrob Chemother 2011;66:1948-53.
Infectious Diseases Society of America. Bad drugs, No Drugs. Alexandria, Virginia. Infectious Diseases Society of America; 2004.
Sabiha I, Twinkle G, Aarti A, Nilanjan D. A comparative study of an antimicrobial profile having broad-spectrum bacteriocins against antibiotics. Asian J Pharm Clin Res 2017;10:44-7.
Antibiotics research: problems and perspectives Statement. Academy of Sciences and Humanities in Hamburg German National Academy of Sciences Leopoldina; 2013.
Hellen G, Molly MP, Suraj P, Sumanth G, Jordan L, Devra B, et al. State of the World’s Antibiotics: CDDEP; 2015.
Sadiya Z, Syed B, Shym N, Tanveer A, Faaiza Q. Synergistic combinations of broad-spectrum antibiotics against acinetobacterspp. Int J Pharm Pharm Sci 2015;7:214-7.
Conly JM, Johnston BL. Where are all the new antibiotics? The new antibiotic paradox. Can J Infect Dis Med Microbiol 2005;16:159-60.
Dalhoff A. Resistance surveillance studies: a multifaceted problem-the fluoroquinolone example. Infection 2012;40:239–62.
Lübbert C, Becker RD, Rodloff AC, Laudi S, Busch T, Bartels M, et al. Colonization of liver transplant recipients with KPC-producing Klebsiellapneumoniaeis associated with high infection rates and excess mortality: a case–control analysis. Infection 2014;42:309–16.
Anthony RM, Gerry H, Yanmin H. Novel classes of antibiotics or more of the same? Br J Pharmacol 2011;163:184–94.
Draenert R, Seybold U, Grutzner E, Bogner JR. Novel antibiotics: are we still in the pre–post‑antibiotic era? Infection 2015;43:145–51.
Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science 2009;325:1089-93.
Ivan DB, Xian Jin, Ricardo V, Daniel P, Sacha J, Bee Ha Gan, et al. Chemical space guided discovery of antimicrobial bridged bicyclic peptides against pseudomonas aeruginosa and its biofilms. Chem Sci 2016;7:1-812.
Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, et al. New antibiotic kills pathogens without detectable resistance. Nature 2015;517:455–9.
Mima T, Brian HK, Drew AR, Malcolm GPP, Eric D, Herbert P, et al. In vitro activity of BAL30072 against Burkholderia pseudomallei. Int J Antimicrob Agents 2011;38:157–9.
New antibiotics acting against resistant microorganisms. Available from: https:/www.google.co.in.novelantibioticsdiagram. [Last accessed on 09 Jul 2017]
Infectious Diseases Society of America (IDSA), Promoting Antimicrobial Stewardship in Human Medicine. Available from: https://www.idsociety.org/Stewardship_Policy/. [Last accessed on 08 Jul 2017]
Lambert PA. Bacterial resistance to antibiotics: modified target sites. Adv Drug Delivery Rev 2005;57:1471–85.
Singh SB, Barrett JF. Empirical antibacterial drug discovery–foundation in natural products. Biochem Pharmacol 2006; 71:1006-15.
Zhanel GG, Schweizer F, Karlowsky JA. Oritavancin: mechanism of action. Clin Infect Dis 2012;54:214–9.
Rubino CM, Van Wart SA, Sujata MB, Paul GA, Jill SM, Alan F. Oritavancin population pharmacokinetics in healthy subjects and patients with complicated skin and skin structure infections or bacteremia. Antimicrob Agents Chemother 2009;53:4422-8.
Belley A, Francis FA, Sarmiento I, Hong D, Warren R, Greg M, et al. Pharmacodynamics of a simulated single 1,200-milligram dose of oritavancin in an in vitro pharmacokinetic/pharmacodynamic model of methicillin-resistant Staphylococcus aureusinfection. J Antimicrob Chemother 2013;57:205–11.
Seltzer E. Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections. Clin Infect Dis 2003;37:1298–303.
Jauregui LE, Simon B, Elyse S, Lisa G, Dainis K, Mark F, et al. Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis 2005;41:1407–15.
Dorr MB, Daniela J, Marco C, James D, Giorgio M, Adriano M, et al. Human pharmacokinetics and rationale for once-weekly dosing of dalbavancin, a semi-synthetic glycopeptide. J Antimicrob Chemother 2005;55:25–30.
Helen WB, Mark W, George HT, Sailaja P, Anita FD, Michael W, et al. Once-weekly dalbavancin versus daily conventionaltherapy for skin infection. N Engl J Med 2014;370:2169–79.
FDA. FDA approves new antibacterial drug Zerbaxa; 2014. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427534.htm. [Last accessed on 08 Jul 2017]
Lemaire S, Tulkens PM, Van Bambeke F. Contrasting effects of acidic pH on the extracellular and intracellular activities of the anti-gram-positive fluoroquinolonesmoxifloxacin and delafloxacin against Staphylococcus aureus. Antimicrob Agents Chemother 2011;55:649–58.
Siala W, Marie P, Francoise V, Paul MT, Marie H, Oliver D, et al. Antibiotic activity against biofilms from Staphylococcus aureus clinical isolates: factors determining the activity of the investigational fluoroquinolone delafloxacin in comparison with daptomycin and vancomycin. Antimicrob Agents Chemother 2014;58:6385–97.
Citeline. “Pharmaprojects; 2012. Available from: http://www. citeline.com/products/pharmaprojecs. [Last accessed on 08 Jul 2017].
Helen WB, George HT, Daniel KB, John B, Robert JG, et al. “10 x ’20 progress—development of new drugs active against gram-negative bacilli: an update from the infectious diseases society of America. Clin Infect Dis 2013;56:1685–94.