DISCOVERIES 2018, Jan-Mar, 6(1): e81 DOI: 10.15190/d.2018.1 FDA Approved Antibacterial (2015-2017)

Focused REVIEW

New FDA approved antibacterial drugs: 2015-2017

Stefan Andrei#,1,*, Liana Valeanu#,2,3, Radu Chirvasuta4, Mihai-Gabriel Stefan 2,3 ‘ 1Intensive Care Unit, Centre Hospitalier Lyon Sud, Pierre Benite, France 2Department of Cardiac Anesthesia and Intensive care, Emergency Institute for Cardiovascular Diseases “Prof. C.C. Iliescu” Bucharest, Romania 3Carol Davila University of and Pharmacy, Bucharest, Romania 4Anaesthetics Department, Lister Hospital, Stevenage, UK

# These authors contributed equally to this manuscript * Corresponding author: Stefan Andrei, MD, , Centre Hospitalier Lyon Sud, Pierre Benite, France, [email protected]

Submitted: March 29, 2018; Revised: March 31, 2018; Accepted: April 3, 2018; Published: April 4, 2018; Citation: Andrei S, Valeanu L, Chirvasuta R, Stefan MG. New FDA approved antibacterial drugs: 2015-2107. Discoveries 2018, January-March; 6(1); e81. DOI:10.15190/d.2018.1

ABSTRACT structure . Despite recent progress, it is Increasing bacterial resistance to is a imperative to continue the development of new worldwide ongoing issue. Urgent need for new drugs and new strategies to counteract antibacterial agents has resulted in significant resistance to antibiotics. research efforts, with new molecules proposed for use in clinical practice. However, as highlighted by Keywords: many groups this process does not have an optimal FDA approved drugs, , , rhythm and efficacy, to fully combat highly adaptive , , , germs, particularly in the intensive care units. , vabomere, ozenoxacin, malacidin, This review focuses on the last three years of novel , 2015, 2016, 2017. FDA approved antibacterial agents (2015-2017): ceftazidime/avibactam, obiltoxaximab, bezlotoxu- Abbreviations: mab, delafloxacin, /vaborbactam, and Administration (FDA); European ozenoxacin. Ceftazidime/avibactam and meropenem/ Agency (EMA); Area under the curve (AUC); New Delhi metallo-β-lactamase (NDM); Verona integron- vaborbactam are new players in the field of resistant encoded metallo-β-lactamase (VIM); Imipenmase (IMP); treatment. Ceftazidime/avibactam is Complicated intra-abdominal infections (cIAIs); validated in selected patients with complicated Complicated urinary tract infections (cUTIs); Hospital urinary or intra-abdominal infections, hospital and acquired bacterial (HABP); Ventilator ventilator-associated pneumonia. Meropenem/ associated (VABP); Acute bacterial vaborbactam gained approval for the cases of skin and skin structure infections (ABSSI); Intravenous (IV); Central Nervous System (CNS); Hours (h); complicated urinary tract infections. Other potential indications are under investigation, widened and 1. Introduction validated by future studies. Obiltoxaximab is a monoclonal that can be used in the Antibiotics discovery and clinical use is undoubtedly prevention and treatment of inhalational . one of the pillars of modern medicine. Modern Bezlotoxumab is an useful and medicine saw a continuous competition between specific tool for the management of recurrent new antibacterial drug research and the ability of Clostridium difficile . Delafloxacin is bacteria to develop resistance1. New classes of approved for patients with acute skin or skin antibiotics were created, old drugs regained interest www.discoveriesjournals.org/discoveries 1 FDA Approved Antibacterial Drugs (2015-2017) and paradigm changes were proposed2–4. However, therapeutic armamentarium. New antibacterial this process seems to have diminished its pace and, agents were identified using FDA after less than a century since the first clinical use of (www.accessdata.fda.gov, www.fda.gov) and Center an antibiotic, bacterial resistance to antibiotics is a Watch sites (https://www.centerwatch.com/drug- major concern of current medical practice and information/fda-approved-drugs/). research5. The great offers an The number of FDA-approved antibacterial unfortunate insight of a post-antibiotic era. drugs and the total novel molecules for each year In the intensive care unit, dealing with during the past 15 years is summarized in Figure 1. resistant bacteria is a daily struggle. A careful A tendency of increasing the number of approved antibiotic stewardship combined with public health molecules by year can be noticed. Furthermore, prevention measures are vigorously promoted, in visibly more antibacterial molecules have been order to lower the of resistant bacteria2,6–9. approved in recent years compared with previous Despite sustained efforts, some bacteria highly years. susceptible to develop resistance, such as To the date of this review, no antibacterial aeruginosa or Acinetobacter drug has been approved for 2018, from a total of 6 baumannii, end up being treated by not so new drugs newly introduced molecules. In 2017, the 3 like colimycin3,10,11. From this perspective, the approved antibacterial drugs represented 6.5% of the intensive care physician is looking regularly to the total of 46 new drugs. 2016 brought 2 new drugs, research field, expecting an ideal antibiotic: specific, respectively 9% of the 22 approved molecules. In effective, well tolerated and with no long term 2015, only one antibacterial agent was approved by induced resistance. FDA (2.2% from a total of 45). In this present review, we briefly address the We identified 6 novel FDA approved new antibacterial agents approved during the recent antibacterial drugs: the 3rd generation years by FDA, as a hope to reinforce the current and β-lactamase inhibitor combination

Figure 1. Novel FDA-approved antibacterial and non-bacterial drugs by year (last 15 years)

www.discoveriesjournals.org/discoveries 2 FDA Approved Antibacterial Drugs (2015-2017) ceftazidime/avibactam in 2015; two monoclonal : , , obiltoxaximab and bezlotoxumab in pneumoniae, , Enterobacter 2016; a new fluoroquinolone, delafloxacin, a cloacae, Klebsiella oxytoca, Citrobacter freundii combination of meropenem with the β-lactamase complex and , in patients inhibitor vaborbactam, vabomere, and a non- 18 years or older, based on clinical trials which fluorinated quinolone, ozenoxacin, all in 2017 proved its non-inferiority when compared to (Table 1). These drugs are briefly discussed further carbapenems17,18,19. In complicated intra-abdominal by FDA-approval year. infections, combination of ceftazidime/avibactam and is 2. FDA approved antibacterial drugs (2015-2017) recommended15,17. Recent approval for hospital-acquired 2.1 Ceftazidime/avibactam bacterial pneumonia and ventilator-associated Ceftazidime/avibactam is a combination of bacterial pneumonia based on the Reprove study, a ceftazidime, a third generation cephalosporin, with phase 3, multicenter, double-blind, randomized trial avibactam, a β-lactamase inhibitor12. Ceftazidime which included 870 patients, make inhibits synthesis by inhibiting ceftazidime/avibactam a viable therapeutic option -binding , resulting in for hospital-acquired pneumonia20. instability and cell death13. Avibactam is a synthetic Ceftazidime/avibactam might be valuable for non-β-lactam β-lactamase inhibitor that inhibits the the Intensive Care Unit (ICU) patient when is also 6 activities of Ambler class A and C β-lactamases used as carbapebem-sparing antibiotic . However, a and of some Ambler class D , but not the retrospective case series argued the quick emergence 21,22 B1 metallo-β-lactamases, such as the New Delhi of resistance in treated patients . metallo-β-lactamase (NDM), Verona integron- encoded metallo-β-lactamase (VIM) and 2.2 Obiltoxaximab Imipenmase (IMP)14. Obiltoxaximab is a monoclonal antibody directed against the protective (PA) of Bacillus Cmax and area under the curve (AUC) of anthracis, thus preventing it from binding to cellular ceftazidime proportionally increase with the dose; receptors23. It is a chimeric agent, consisting of avibactam demonstrates linear enhanced 14B7V and V connected to human across the dosage range15. Ceftazidime, as well as H L avibactam, are excreted via kidneys as unchanged ν1 and K constants, which was derived from the drugs15. Less than 10% of ceftazidime and 5.7% to murine monoclonal antibody 14B7, with 8.2% of avibactam are bound15. Volumes of resulting in a 50-fold increase in affinity and 24 distribution of ceftazidime and avibactam are 17 L corresponding neutralizing capability . and 22.2 L respectively15. Obiltoxaximab is the second monoclonal In patients with impaired renal function, the antibody approved for the treatment of inhalational half-life of ceftazidime is prolonged and a anthrax, the other being raxibacumab25. It can be dosage adjustment is recommended16. Moreover, in administered as pre-exposure prophylaxis, in which patients with complicated intra-abdominal infections case it is the only therapeutic option, and in and creatinine clearance of 30-50 ml/min, confirmed cases in combination with the appropriate ceftazidime/avibactam has been found to have lower antimicrobials24. efficacy17. As clinical trials with intentional exposure of Adverse reactions that have been described humans to anthrax are unethical, its efficacy was are reactions, including , examined in multiple studies conducted in two Clostridium difficile-associated and Central models of inhalational anthrax, including Nervous System reactions, such as seizures, New Zealand White rabbits (two studies) and especially in patients with renal impairment15. cynomolgus macaques (4 studies) at disease onset Ceftazidime/avibactam is indicated for the following lethal challenge with aerosolized Bacillus treatment of complicated intra-abdominal infections anthracis spores26. In these studies, obiltoxaximab and complicated urinary tract infections caused by monotherapy neutralized PA and increased survival the following susceptible Gram-negative across the range of disease severity, indicating www.discoveriesjournals.org/discoveries 3 FDA Approved Antibacterial Drugs (2015-2017) clinical benefit of neutralization in both early 2.4 Delafloxacin and late stages of inhalational anthrax26,27. Delafloxacin is a new fluoroquinolone with a The human dose was selected and justified by potential role in the treatment of acute bacterial skin comparing observed drug exposures in to and skin structure infections, in adults. It was shown observed exposures in healthy and infected to be active against Gram‐positive (Staph. humans28. In humans at a dose of 16 mg/kg IV aureus, including -resistant, methicillin- obiltoxaximab AUC was >2 times that in animals, susceptible isolates, Staph. haemolyticus, Staph. while maximum serum concentrations were lugdunensis, Strep. agalactiae Strep. anginosus comparable28. group and faecalis) and some Gram- Obiltoxaximab has a black box warning due negative bacteria (Escherichia coli, Enterobacter to severe hypersensitivity reactions that have been cloacae, , Pseudomonas reported during infusion, including anaphylaxis; a aeruginosa)39. premedication with diphenhydramine is Its consists of inhibition recommended23. Although not yet approved, recent of the activity of bacterial DNA IV studies on humans using obiltoxaximab via and DNA gyrase (topoisomerase II), thus interfering intramuscular route showed good efficacy with no with bacterial DNA replication by preventing the hypersensitivity reactions29. relaxation of positive supercoils introduced as part of the elongation process40. Due to its chemical 2.3 Bezlotoxumab structure, delafloxacin is weakly acid, unlike other Bezlotoxumab is a fully human monoclonal IgG1 fluoroquinolones, thus displaying a preserved antibody directed against Clostridium difficile toxin antibacterial action through a reduced minimum B30. Bezlotoxumab exerts its action by impeding the inhibitory concentration in environments with low binding of toxin B to colonic cells and consequently pH40. It is highly protein bound (84%), primarily to preventing development of C. difficile infection31. albumin, has a large distribution volume (48 L) and By neutralizing the toxin B, bezlotoxumab has a half-life of 3.7-8.5 hours, with a peak serum attenuates pro-inflammatory responses and concentration of 7.45 mg/L after a 1 hour infusion40. reduces damage to epithelial tissue of colonic Its clearance is ensured in approximately equal explants32,33. It has no direct activity proportions by renal and non-renal pathways40. against C. difficile, it has low immunogenicity and is Delafloxacin received FDA approval after generally well tolerated34. Recent data suggest that it demonstrating its non-inferiority to the combination is also cost-effective when administered together of and in two phase 3 with standard-of-care antibiotics35. studies, in adult patients with acute bacterial skin FDA approval in October 2016 was obtained and skin structure infections (PROCEED Study based on two double-blind, randomized, placebo- Group)41,42,43. Its efficacy in community-acquired controlled, phase 3 clinical trials, Modify I and II, bacterial pneumonia is currently under investigation which involved 2655 adults treated for primary or in a phase III (NCT02679573)44. recurrent C. difficile infection. In these trials, The drug is contraindicated in patients with bezlotoxumab was associated with a lower rate of known hypersensitivity to delafloxacin or any of the recurrent infection and had a safety profile similar to fluoroquinolone class of antibacterial drugs. Its that of placebo36. Based on the population studied in common side effects include , diarrhea, the trials, it has been proposed that the risk factors headache, transaminase elevations and vomiting43. justifying treatment with bezlotoxumab are: age over Of note, FDA issued a black box warning related to 65 years, history of previous C. difficile infection, the risk of tendinitis, rupture, peripheral immunosuppression and presence of virulent strain neuropathy, CNS effects, exacerbation of or severe C. difficile infection 37. myasthenia gravis, hypersensitivity reactions and Another monoclonal antibody, , Clostridium Difficile-associated diarrhoea40,43. directed against C. difficile toxin A, is available38. Unlike other fluoroquinolones, it does not Modify trials did not show any benefit in adding seem to elevate the risk of QTc interval actoxumab to bezlotoxumab. On the contrary, the prolongation on the EKG, or phototoxicity. Its use rates of sustained were lower compared to appears to be safe in patients with renal disease or bezlotoxumab alone36. hepatic impairment40,43,45,46. www.discoveriesjournals.org/discoveries 4 FDA Approved Antibacterial Drugs (2015-2017)

TABLE 1. Main characteristics of the described antibacterial drugs15,16,23,30,31,34, 43,47,53

NAME Approval status Indication Administration Dose and duration (generic/brand/ class) Ceftazidime/avibactam / FDA: CIAIs, cUTIs, Ceftazidime 2g 1. For cIAIs and cUTIs, avycaz (USA), zavicefta 1. since 2015 in combination HABP, VABP and avibactam ceftazidime 2g / (Europe) / combination with metronidazole (cIAIs 0.5g. avibactam 0.5g every 8 of ceftazidime, 3rd cUTIs IV infusion hours, for 5-14 days. generation 2. since 01/02/2018 for HABP over 2h 2. For HABP and VABP, cephalosporin, with and VABP ceftazidime 2g / avibactam, a β-lactamase EMA: avibactam 0.5g /8h for 7- inhibitor 1. since 2016 for cIAIs, cUTIs, 14 days. COMPANY: Allergan HABP, VABP 3. Adaptation of doses in Inc (USA), 2. infections due to aerobic case of renal function (Europe) Gram-negative organisms impairment. (adults - limited options) Obiltoxaximab/ Anthim/ FDA: approved in March 2016 Inhalational Diluted in 0.9% Adult patients 16 mg/kg. Monoclonal antibody EMA: not approved anthrax Sodium In paediatric patients, COMPANY : Elusys Chloride,IV weight adaptation needed, Therapeutics infusion over 1 greater than 40 kg - 16 hour and 30 mg/kg, 15 to 40 kg - 24 minutes mg/kg, less than or equal to 15 kg - 32 mg/kg Bezlotoxumab/ Zinplava/ FDA: Approved in October Prevention of Diluted solution Recommended dosage is Monoclonal antibody 2016 CDI iv infusion over 10 mg/kg. COMPANY: EMA: Approved in January recurrence, in 60 min using a Not evaluated in patients Merck Sharp & Dohme 2017 >18 years old low-protein below 18 years of age Limited patients with binding 0.2-5 antibiotic ther. µm in-line or add-on filter. Delafloxacin/ Baxdela/ FDA: approved in June 2017 ABSSI IV infusion or 300 mg/12h for 5-14 days fluoroquinolones for ABSSI oral use iv infusion over 1h COMPANY: EMA: application in March 450 mg/12h orally for 5 to Melinta Therapeutics 2018 14 days. Renal adaptation needed. Meropenem- FDA: approved in August 2017 cUTI, Single-dose 4g administered over 3 Vaborbactam/ for adults with cUTI, including including vials containing hours by intravenous Vabomere/ combination pyelonephritis 2 g (1 g infusion every 8 hours for of meropenem, and EMA: marketing authorization meropenem and up to 14 days. vaborbactam, a β- application submitted in July 1 g Renal adaptation needed. lactamase inhibitor 2017 vaborbactam) COMPANY: Melinta as a sterile, dry Therapeutics powder (iv) Ozenoxacin/ xepi/ non- FDA: approved in Dec. 2017 Pale-yellow 1% Topically applications to fluorinated quinolone for the treatment of impetigo , the affected area twice a COMPANY: Staph. Aureus, Strept. Topical use day for 5 days Medimetrics Pharm. pyogenes (> 2 months old) only

Food and Drug Administration (FDA), European Medicines Agency (EMA), complicated intra-abdominal infections (cIAIs), complicated urinary tract infections (cUTIs), hospital acquired bacterial pneumonia (HABP), ventilator associated bacterial pneumonia (VABP), acute bacterial skin and skin structure infections (ABSSI), intravenous (iv), hours (h), therapy (ther.)

www.discoveriesjournals.org/discoveries 5 FDA Approved Antibacterial Drugs (2015-2017)

2.5 Vabomere The drug is contraindicated in patients with Vabomere is the first combination of a hypersensitivity to any of the two components or to and a β-lactamase inhibitor, consisting of other drugs in the same class, and the most meropenem, a broad carbapenem frequently encountered adverse reactions include antibacterial, and vaborbactam, a β-lactamase headache, phlebitis or infusion site reactions, and inhibitor approved by the FDA in August 2017 for diarrhea47. Rare but severe side effects include the treatment of complicated urinary infections hypersensitivity reactions, seizures (especially in (including pyelonephritis) in adult patients47. patients treated with valproic acid), Clostridium Meropenem-susceptible microorganisms difficile-associated diarrhea, , include Gram-negative bacteria like Escherichia neuromotor impairment, development of drug coli, Klebsiella pneumoniae, Enterobacter cloacae resistant bacteria and overgrowth of nonsusceptible species complex or Pseudomonas aeruginosa48. organisms49. Precautions should be taken and doses After binding to penicillin-binding proteins, should be adapted for the patients with renal meropenem inhibits the final step of peptidoglycan function impairment53. synthesis in bacterial cell walls and thus the biosynthesis of cell walls, leading to bacterial lysis49. 2.6 Ozenoxacin Vaborbactam, a β-lactamase inhibitor, has no Ozenoxacin, a non-fluorinated quinolone, received antibacterial efficacy on its own, but it blocks FDA approval in December 2017 for the topical carbapenemases produced by Klebsiella pneumoniae treatment of impetigo caused by Staphylococcus and other β-lactamases, which could cause aureus or pyogenes in adult and degradation of meropenem, thus leading to in vitro pediatric patients older than 2 months54. activity against nearly all (99%) of Klebsiella The drug is bactericidal against susceptible pneumoniae carbapenemase producing microorganisms through inhibition of bacterial DNA Enterobacteriaceae49. replication enzymes, DNA gyrase A and Meropenem is 2% protein bound, has a topoisomerase IV54. After topical application, the distribution volume of 20.2 L and a half-life of 2.3 majority of ozenoxacin plasma samples were below hours49. Vaborbactam is 33% protein bound, has a the limit of quantification, suggesting no systemic distribution volume of 18.6 L and a half-life of 2.2 absorption. Thus, the distribution, and hours49. While vaborbactam is not well of ozenoxacin have not been investigated metabolized and is excreted in the urine over a 2 in humans55. day period, approximately 30% of the meropenem FDA approval was granted after a phase 3 dose is metabolized by hydrolysis of the β-lactam randomized, double-blind, multicenter study proved ring to an inactive form, which is excreted in the the efficacy and safety of ozenoxacin in the urine, and between 40-60% of the meropenem dose treatment of impetigo56. Adverse reactions, such as is excreted unchanged within 2 days49. or seborrheic , were rarely Meropenem-vaborbactam received FDA reported, but prolonged use may result in approval after demonstrating its superiority over overgrowth of nonsusceptible bacteria and fungi54. piperacilline- for the treatment of complicated urinary tract infections, including acute 3. under investigation pyelonephritis, in a phase 3, multicenter, randomized, double-blind, double-dummy study Other drugs or combinations are in different stages including 550 patients (TANGO I trial)50. Due to its of clinical research. World Health organization activity against multi-drug resistant bacteria, extensively reviewed, from a global health meropenem-vaborbactam shows promising perspective, the antibacterial agents in clinical implications in the treatment of ventilator-associated development in 2017, with focus on innovativeness pneumonia (TANGO II trial)51,52. A phase III, and expected activity on priority pathogens57. multicenter, prospective, randomized, double- Despite the total number of 33 new antibiotic entities blinded TANGO III trial comparing vabomere and 9 new biological agents targeting global priority and piperacilline/tazobactam in hospital-acquired pathogens, the 7 drugs against or ventilator-associated pneumonia is launced and and the 9 agents against C. difficile, the estimated to be completed in 2010 (NCT03006679). review noticed an insufficient “clinical pipeline” and www.discoveriesjournals.org/discoveries 6 FDA Approved Antibacterial Drugs (2015-2017)

“a lack of potential treatment options for priority depsipeptide, first identified by Ling et al. in 2015, resistant bacteria, especially for multidrug- and which possesses a very strong inhibitory action on extensively drug-resistant Gram-negative peptidoglycan synthesis63. New species of β- pathogens”, including resistant to anti-tuberculosis proteobacteria temporarily named Eleftheria terrae treatment57. have been used during the process63. This molecule A recent article by Bassetti M. et al. reviews proved to be extremely potent in vitro against the potential drugs in treating ventilator-associated , including methicillin- pneumonia51. Beside the already FDA-approved resistant variants (minimal inhibitory concentration (2014), ceftolozane/tazobactam (2014), (MIC) 0.25 mcg/ml), Mycobacterium tuberculosis ceftazidime/avibactam (2015) and (MIC 0.125 mcg/ml), Vancomycin-resistant meropenem/vaborbactam (2017), there are studies Enterococcous faecium (MIC 0.5 mcg/ml), concerning , /, Clostridium Difficile (MIC 5 ng/ml) and Bacillus ceftaroline/avibactam, aztreonam/avibactam, anthracis (MIC20 ng/ml), but not on Gram-negative , eravacyclin, murapavadin51. From this bacteria63. During this study, no resistance was list, cefiderocol stands out, since its FDA and EMA observed and teixobactin shown good efficacy and approvals are expected in 201858. tolerance in methicillin-resistant Staphylococcus Cefiderocol, also known as S-649266, is a aureus (MRSA) induced- mice models63. cephalosporine showing potency against This strong bactericidal effect can be Gram-negative bacteria58. A particular capacity to explained by its ability of blocking the cell wall chelate iron makes it able to penetrate the outer synthesis through synergistic inhibition of bacterial membrane through bacterial iron- peptidoglycan and formation, by transporting systems59. A large study using clinical binding the precursor lipid II and lipid III, causing collections from North America and Europe cell wall injury and the destruction of bacterial cell64. evaluated the bacterial spectrum of cefiderocol and No study in humans has yet been performed and the found a good activity against Gram-negative road to clinical practice might be long, but there are bacteria, even for resistant species, like hopes that this new class could be the long meropenem-non susceptible awaited solution for the burden of MRSA and VRE (MIC <4 mcg/ml for 97% of isolates)60. This effect (Vancomycin-resistant Enterococcus) infections, as was also noted for Pseudomonas aeruginosa and, well as for the resistant strains of Mycobacterium interestingly, for Acinetobacter baumanni, making tuberculosis65. this new molecule particularly valuable in the case Another newly discovered antibiotic class of difficult to treat resistant infections60. 3 Phase III using a culture-independent approach are the clinical trials are evaluating the potential role and malacidins, Hover et al. publishing their results in safety of cefiderocol in treating carbapanem- 201866. The malacidins have a lipopeptidic structure, resistant enterobacteria infections, ventilator with protidic core, which includes 4 non- associated pneumonia or urinary tract infections, and proteinogeic aminoacids66. The 10 members of this their results are awaited with interest class are differentiated by a methylene group at the (NCT02714595, NCT03032380, NCT02321800). end of the lipidic branch66. Malacidin A revealed a Recently, the future perspectives in calcium-dependent bactericidal in vitro and in vivo antimicrobial research have become a little more effect on Gram-positive bacteria like Staphylococcus optimistic. Description of a specific isolation chip aureus, including vancomycin-resistant variants. No by Nichols et al. that allows the identification of new resistance was detected66. As in the case of antibiotic sources in microorganisms has opened teixobactin, the potential clinical benefit is the gates for new discoveries61. Antimicrobial significant and the of the studies on discovery had been significantly slowed down by the malacidins is followed with a great interest. difficulties in culturing environmental microorganisms that were concerning 99% of the 4. Conclusion species62. These methodological improvements lead to the discovery of new classes of antibiotics. One The last 3 years brought new antimicrobial drugs very promising anti-Gram-positive bacteria recently available for clinical use. Some agents like described is teixobactin, an 11-residue, macrocyclic obiltoxaximab, bezlotoxumab antibodies and www.discoveriesjournals.org/discoveries 7 FDA Approved Antibacterial Drugs (2015-2017) ozenoxacin target narrow areas of interest. Future 8 Álvarez-Lerma, F. et al. Prevention of Ventilator- studies and clinical practice will define the place of Associated Pneumonia: The Multimodal Approach of delafloxacin among the other acute skin infection the Spanish ICU “Pneumonia Zero” Program. Crit. treatments, and likewise concerning the role of the Care Med. 2018; 46(2):181-188. new combinations - ceftazidime/avibactam and 9 Derde, L. P. G et al. Interventions to reduce colonisation and of antimicrobial- meropenem/vaborbactam - in the practical resistant bacteria in intensive care units: an interrupted management resistant bacterial infections in the time series study and cluster randomised trial. Lancet Intensive Care Unit. The recent discovery of new Inf. Dis. 2014, 14: 31–39. antibiotic classes and the augmentation of the source 10 Jacobs, M. et al. Population pharmacokinetics of pool for further research have brought a glimmer of methanesulfonate and colistin in critically ill optimism. But the road to actual clinical benefit patients with acute renal failure requiring intermittent might be long and the past experience has taught us hemodialysis. Antimicrob. Agents Chemother. 2016, that resistance can develop even for very promising 60: 1788–1793. molecules. A shared and vigorous research effort is 11 Ruppé, É., Woerther, P.-L. & Barbier, F. Mechanisms continuously needed in order to improve the of in Gram-negative bacilli. Ann. Intensive Care 2015, 5: 21. therapeutic options for the increasingly resistant and 12 Zhanel, G. G. et al. Ceftazidime-Avibactam: a Novel highly adaptable germs. Cephalosporin/β-lactamase Inhibitor Combination. Drugs 2013, 73: 159–177. Acknowledgments 13 Lagacé-Wiens, P., Walkty, A. & Karlowsky, J. We are grateful to the Centre Hospitalier Lyon Sud, Ceftazidime and avibactam: an evidence-based review Pierre Benite, France for support. of its and potential use in the treatment of Gram-negative bacterial infections. Core Evid. 2014, 13. doi:10.2147/CE.S40698 Conflict of interests 14 Levasseur, P. et al. In Vitro Antibacterial Activity of The authors declare no conflicts of interest. the Ceftazidime-Avibactam (NXL104) Combination against Pseudomonas aeruginosa Clinical Isolates. References Antimicrob. 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