FDA approved antibacterial drugs: 2018-2019

Bacterial resistance to existent antibiotherapy is a perpetual internationally-recognized problem. Year after year, there is a continuous need for novel antibacterial drugs and this research and development efforts recently resulted in few new drugs or combination of drugs proposed for the use into the clinic. This review focuses on the novel US FDA approved antibacterial agents in the last two years (2018-2019). Plazomicin, eravacycline, sarecycline, omadacycline, rifamycin (2018) and imipenem, cilastatin and relebactam combination, pretomanid, lefamulin, cefiderocol (2019) are new therapeutic options. Plazomicin aminoglycoside antibiotic targets Enterobacteriaceae infections, being mainly used for the complicated urinary tract infections. The fully synthetic fluorocycline eravacycline gained approval for the complicated intra-abdominal infections. The tetracycline-derived antibiotic sarecycline might be a useful strategy for the management of non-nodular moderate to severe acne, while the other tetracycline-derived antibiotic approved, omadacycline, may be used for the patients with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. The already-known RNA-synthesis suppressor rifamycin is now also approved for noninvasive Escherichia Coli-caused travelers' diarrhea. Two combinatorial strategies were approved for complicated urinary tract infections, complicated intra-abdominal infections (imipenem, cilastatin and relebactam) and lung tuberculosis (pretomanid in combination with bedaquiline and linezolid). Lefamulin is a semisynthetic pleuromutilin antibiotic for community-acquired bacterial pneumonia, while cefiderocol, a cephalosporin antibiotic is the last antibacterial drug approved in 2019, for the use in complicated urinary tract infections. Despite of these new developments, there is an ongoing need and urgency to develop novel antibiotic strategies and drugs to overrun the bacterial resistance to antibiotics.


Introduction
The run to overcome the rapid bacterial resistance started with the initial use of antibiotics. However, after decades of struggling in research and in clinical practice, this run is rather a marathon than a sprint.
Despite sustained efforts, the physicians are continuously confronting worldwide with the threat of bacterial resistance [1][2][3] . The burden on public health contributed to the creation and implementation of strategies on rational antibiotic use and on limiting the spread of resistant bacteria, the so called antibiotic stewardship [4][5][6][7] .
Other strategy in this direction is to optimize the existing pharmaceutical arsenal, through novel combinations and new indications 8 . However, the number and efficiency of these drugs is far from covering all the existing needs and to fully combat the highly adaptive bacterial microorganisms.
Moreover, pan-resistant bacteria emergence has been already described 9,10 . Other evidences further consider the non-negligible role of environmental and agriculture-related factors 11,12 .
Antibiotic stewardship has proved its efficiency, but it has its own limits and challenges [13][14][15] . However, the quest for new efficient molecules have to continue, remaining a pillar of antimultidrug resistant germs strategy 16 .
We briefly review here the novel antibacterial agents approved by the United States Food and Drug Administration (US FDA) during the past 2 years (2018 and 2019) with the hope to further encourage the scientific community in continuing the development of new therapeutic agents for targeting the resistance of bacteria. The recently approved antibacterial drugs and drug combinations were identified using FDA's website (https://www. accessdata.fda.gov; www.fda.gov) and Center Watch's site (https://www.centerwatch.com/druginformation /fda-approved-drugs/).
We reviewed the total number of drugs and drug combinations (blue) and number of antibacterial drugs and drug combinations (red) approved by the US FDA in the past 17 years  17 ) and modified from 17 ). There is a clear upward trend in terms of the number of antibacterial drugs approved by year.
To the date of this review, 9 antibacterial drugs or combination of drugs were approved for 2018 and 2019, from a total of 107 introduced molecules. In 2018, the 5 approved antibacterial drugs or combinations of drugs represented 8.4% of the total of 59 new drugs, while in 2019 the 4 new single or combination of antibacterial drugs represented 8.33% of the 48 approved molecules. This represents a significant increase from the previous years (Figure 1), since the number of antibacterial drugs or regimens in the past two years has doubled as compared to the two previous years.

Plazomicin
Plazomicin sulfate (Zemdri) is a semisynthetic aminoglycoside bactericidal antibiotic drug, acting in asimilar manner to other aminoglycosides, by suppressing the 30S bacterial ribosomal subunit. Noteworthy, while other aminoglycosides can be inactivated by aminoglycoside-modifying enzymes, plazomicin is resistant to the action of these enzymes 18 .
Plazomicin was approved by FDA in June 2018, for targeting the infections with Gramnegative aerobic bacteria in the complicated urinary tract infections (cUTIs). Application was submitted for review by European Medicine Agency (EMA) in June 2018.
Plazomicin is administered intravenously (IV) every 24 hours for 4-7 days; it is primarily active against Gram-negative aerobic bacteria (e.g. Enterobacteriaceae family), to be used in patients over 18 years of age with cUTIs (including pyelonephritis), caused by susceptible Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis or Enterobacter cloacae 18,19 .
Plazomicin is supplied as single-dose vials in an amount of 500 mg/10 mL plazomicin base 19 . Administration recommendations can be found in Table 1 and its dosage is personalized based on the renal function and/or therapeutic monitoring of the drug, if available 19 . Plazomicin might be of value in patients that have resistance to their primary treatment options or who are allergic to beta-lactam antibiotics.
The most important adverse events reported with plazomicin are: nephrotoxicity (but lower incidence of nephrotoxicity than colistin), diarrhea, hypertension, headache, nausea, vomiting, hypotension 20 .

Eravacycline
Eravacycline dihydrochloride (Xerava) is a fully synthetic bacteriostatic fluorocycline and a tetracycline-class antibacterial agent that binds bacterial 30S ribosomal subunit. Compared to other tetracyclines, it has two structural substitutions which makes the drug working on certain strains of Gram-positive and Gram-negative bacteria that usually have tetracycline-specific resistance mechanisms. Noteworthy, eravacycline can be used (at least in cell culture) to target Enterobacteriaceae, in the presence of certain beta-lactamases 18,22 .
Eravacycline was approved by FDA in August 2018 and by EMA in September 2018, being indicated in the complicated intra-abdominal infections [22][23][24] .
Eravacycline is administered IV in 60 min infusions, given once every 12 hours for a total of 4 to 14 days; dose is patient's weight dependent (1mg/kg) and it is used in persons over 18 years of age with complicated intra-abdominal infections (cIAI) caused by susceptible microorganisms identified in the prescribing information. This is the only indication of use for eravacycline at this moment, although it may be approved for other applications in the future, similar to other tetracyclines 18 .
The most important adverse event reported with eravacycline in clinical trials and sometimes a cause of the treatment discontinuation is the gastrointestinal (GI) upset. Other noteworthy adverse events that can appear are infusion site reactions, nausea, and vomiting 18,22 .
Eravacycline was compared with ertapenem and meropenem for the treatment of cIAIs in 2 noninferiority trials (IGNITE1 and IGNITE4), with similar clinical response rates 25,26 .

Sarecycline
Sarecycline hydrochloride (Seysara) is a new, narrow-spectrum tetracycline derivative. It proves antibacterial activity against skin and soft tissue pathogens, including the Cutibacterium acnes (anaerobic Gram-positive bacterium related to acne development). Similar to other tetracyclines, it possesses anti-inflammatory effects. However, it has some specific properties comparing to other tetracyclines: it seems to affect the intestinal flora less; it shows a lower rate of resistance to tetracycline-resistant Staphylococcus aureus, as well as erythromycin-resistant and clindamycin-resistant Cutibacterium acnes strains 27 . Sarecycline has significant effects on inflammatory lesions. However, it was also noted to show statistically significant effects on noninflammatory acneiform lesions at certain time points 28 .
Sarecycline was approved by FDA in October 2018, for the treatment of non-nodular moderate to severe acne. Application was also submitted for review by European Medicine Agency (EMA) in October 2018.
The drug is administrated as 1.5 mg/kg/day orally with food, in patients aged 9 and older, as a once daily antibiotic with statistically significant improvement seen as early as 3 rd week. More detailed information about its administration can be found in Table 1.
In clinical trials comparing with placebo evaluating the adverse effects, nausea was reported in 3.1% of the patients treated with sarecycline versus 2.0% in patients treated with placebo; the other adverse reactions reported were found in less than 1% of female subjects treated with sarecycline: vulvovaginal mycotic infection (0.8%) and vulvovaginal candidiasis (0.6%) 29 .

Omadacycline
Omadacycline (Nuzyra) is an aminomethylcycline antibiotic belonging to the tetracycline class. It inhibits 30S bacterial ribosomal subunit. Compared to other tetracycline antibiotics, omadacycline has structural modifications at the C9 and C7 positions of the core tetracycline rings, enabling ribosomal protection mechanisms and stability in the efflux pump related to resistance to the tetracycline antibiotics 30 .
Omadacycline was approved by FDA in October 2018 for the treatment of communityacquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSI) and it is not yet approved by the EMA. It can be administered once-daily in both IV and PO formulations ( Table 1).
Omadacycline has warnings associated with tetracycline-class antibiotics, including: tooth discoloration, enamel hypoplasia and inhibition of bone growth in late pregnancy, infancy, or childhood up to 8 years of age. The most common adverse reactions (incidence ≥2%) seen in clinical trials of omadacycline are: nausea, vomiting, infusion site reactions, alanine aminotransferase increased, aspartate aminotransferase increased, gammaglutamyl transferase increased, hypertension, headache, diarrhea, insomnia, and constipation. Omadacycline has only been studied in patients 18 years of age or older. Omadacycline's affinity for muscarinic M2 receptors induces a transient heart rate increases and it has no effect on the QT interval 31 .
A meta-analysis of randomized controlled trials revealed that the clinical efficacy of omadacycline is not inferior to that of competitor drugs in the treatment of acute bacterial infections in adult patients 32 .

Rifamycin
Rifamycin (Aemcolo) is a bactericidal minimally absorbed antibiotic that inhibits bacterial DNAdependent RNA polymerase, by suppressing RNA synthesis. It is the first antibiotic engineered with Cosmo Pharmaceuticals' Multi Matrix Technology, that enables colonic release of the active compound 33 .  It was approved by FDA in November 2018 for the treatment of the noninvasive strains of Escherichia coli causing travelers' diarrhea, in an orally dose of 388 mg (2 tablets) twice a day for 3 days but not when diarrhea is complicated by fever and/or bloody stools 34. The most important adverse reactions observed during the clinical trials are constipation (3.5%), headache (3.3%), abdominal pain (0.5%) & pyrexia (0.3%) with 1% of the patients discontinuing the treatment 33,34 .
In a randomized double-blind phase 3 study (ERASE), Rifamycin SV-MMX was found to be equally effective as ciprofloxacin and to not induce bacterial resistance to travellers' diarrhea treatment 35 .

Pretomanid
Pretomanid is a nitroimidazole, a class of novel antibacterial agents. It was approved in August 2019 by the FDA to be used in combination with bedaquiline, which targets the adenosine triphosphate (ATP) synthase enzyme of the TB mycobacteria and linezolid, a synthetic antibiotic, the first of the oxazolidinone class, for the treatment of drugresistant TB (lung tuberculosis). It is not yet approved by the EMA.
It is orally administered, one tablet (200 ml) taken once a day for 26 weeks for adults. Specifically, pretomanid 200 mg PO/day x 26 weeks, bedaquiline 400 mg PO/day x 2 weeks, then, 200 mg 3x/week with at least 48 h between doses for x 24 weeks (total of 26 weeks), and linezolid 1200 mg PO/day for 26 weeks 39 .
Adverse events reported with pretomanid include numbness and tingling of extremities, acne, anemia, nausea, vomiting, headache, increased transaminases, excess amylase in the blood, indigestion, decreased appetite, abdominal pain, rash, itching, sharp chest pain during breathing, increased gamma-glutamyl transferases, lower respiratory tract infection, cough, coughing up blood, back pain, visual impairment, low blood sugar (hypoglycemia), abnormal weight loss, diarrhea 40 .
The early efficacy reported in a recently published trial, showed that the pretomanidcontaining regimens had a more significant early bactericidal activity than classical a HRZE regimen 41 . However, more research is needed before pretomanid can be validated as a promising therapy in tuberculosis 42 .

Lefamulin
Lefamulin (Xenleta) is a semisynthetic pleuromutilin antibiotic that binds to the peptidyl transferase center of the 50S bacterial ribosomal subunit, inhibiting protein synthesis within bacteria 43 .
It was approved by FDA in August 2019 for the treatment of CABP. Lefamulin is not yet approved by EMA.
It can be administered either as an IV infusion or PO. It is used as 600 mg orally every 12 hours for 5 days or 150 mg infused IV over 60 minutes every 12 hours for 5-7 days. For additional information please consult Table 2.
As adverse events, lefamulin can prolong the QT interval (increased risk in patients with renal failure or hepatic dysfunction), produces infusionsite reactions, diarrhea, hepatic enzyme elevations, nausea, hypokalemia, insomnia, and headache. There are multiple other drugs interactions and it should not be used in pregnant women 43 .
FDA approval of lefamulin was based on the results of 2 randomized, controlled double-blind, noninferiority trials called LEAP 1 and LEAP 2, which enrolled 1289 adults 44,45 . Results of these trials demonstrated that lefamulin was as effective as moxifloxacin in the treatment of the communityacquired bacterial pneumonia 43 .

Cefiderocol
Cefiderocol (Fetroja) is a siderophore cephalosporin antibacterial drug that has been developed to fight a wide range of bacterial pathogens, such as the βlactam-resistant and carbapenem-resistant organisms 46 .
It was approved in November 2019 for the treatment of complicated urinary tract infections. It is not yet approved by EMA.
It is administered as an IV infusion, 2 gram every 8h, for 7-14 days. Cefiderocol targets a wide range of clinically relevant gram-negative bacteria, including but not limited to the Enterobacteriaceae spp, such as Enterobacter spp, Klebsiella spp, Proteus spp, Vibrio spp, Yersinia spp, Serratia marcescens, Shigella flexneri, Salmonella spp and also nonfermenting bacterial species, such as Acinetobacter and Pseudomonas 46-48 . As adverse effects, cefiderocol is well tolerated, with minor reports of gastrointestinal and phlebitis. This side effect profile is similar to the profile of other cephalosporin drugs 49 .
Clinical trials have shown that Cefiderocol's activity against bacteria non-susceptible for meropenem and Klebsiella pneumoniae carbapenemase-producing Enterobacteriales is similar or even superior to ceftazidime-avibactam. Cefiderocol is also more potent than meropenem and ceftazidime-avibactam in targeting Pseudomonas aeruginosa (against all resistance phenotypes) and Stenotrophomonas maltophilia 49 .

Promising antimicrobials under investigation
Comparing with the last decade, we have the impression of an acceleration of antibiotic succeeded approval. However, this do not meet the urgency of WHO and United Nations calls for action 50 .
At the end of 2019, a total of 42 new antibiotics or new combinations are in different stages of clinical development globally, a certain number being already approved by FDA 51 .Iclaprim stands out by the high possibility of a soon FDA-approval. This molecule with diaminopyrimidine structure acts by inhibiting bacterial dihydrofolate reductase and it has been successfully tested in a phase 3 randomized controlled trial (REVIVE-1), showing to be noninferior to vancomycin in treating ABSSI 52 . By its novel mechanism of action, lack of nephrotoxicity and capacity to suppress bacterial exotoxins, iclaprim might become an interesting player in treating resistant Gram positive germs 53 .
Gram-negative bacteria are protected by a double membrane envelope, which forms a highly efficient barrier to antibiotics. The external membrane contains lipopolysaccharide molecules in the outer layer and integral outer-membrane proteins (OMPs). OMPs are folded into the membrane by a protein complex called the β-barrel assembly machine (BAM), which have a central component called BamA accessible from the bacterial surface. Three recent studies report new antibiotics that seem to target BamA -therefore inhibiting the normal OMP folding that is necessary for bacterial survivaldarobactin, murepavadin analogues and MRL-494. Darobactin was efficient against multiple Gramnegative bacteria (in vitro and in infected mice): polymyxin-resistant Pseudomonas aeruginosa, β-
Murepavadin analogues, obtained after linking the murepavadin molecule with the lipopolysaccharide binding portion of polymyxin B, displayed antibiotic activity against Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli 55 .
MRL-494, a newly identified compound, had similar antibiotic effectiveness in vitro against both wild-type Escherichia coli and a mutant defective in outer-membrane integrity and efflux mechanisms, suggesting that this antibiotic might not need to breach the membrane to exert its activity. However, MRL-494 efficiency remains to be tested in animal models 56 .
Small bacterial toxins can act as antimicrobial peptides. Reducing their toxicity to human cells and retaining their antibiotic activity can open new perspectives in antibiotics development.
Recently, Nicolas et al. synthesized 4 cyclic heptapseudopeptide biomimetics, which reproduce a section of a Staphylococcus aureus toxin, PepA1 57 . Two of the studied peptides were effective against methicillin-resistant Staphylococcus aureus in mild and severe sepsis mouse models without displaying toxicity on human erythrocytes and kidney cells, zebrafish embryos, and mice. Moreover, efficacy was also proved against Pseudomonas aeruginosa and MRSA in a mouse skin infection model. Notably, these novel compounds did not lead to resistance after serial passages for 2 weeks and 4-or 6-days' exposure in mice.
The ability of unnatural amino acids to strengthen dynamic association with bacterial lipid bilayers and to induce membrane permeability can explain the antibiotic effect of the heptapseudopeptides 57 .
Delafloxacin, a new fluoroquinolone already FDA approved for the treatment of acute bacterial skin and skin structure infections, is currently the only antibiotic with in vitro activity against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa 17,58 . Therefore, delafloxacin efficiency in community-acquired pneumonia has been evaluated in recently completed Phase 3 study (NCT02679573).
Ceftobiprole medocaril, an anti-MRSA cephalosporin indicated for the treatment of complicated skin infections and community/hospital acquired pneumonia, it is still unapproved by the FDA, but currently used in some European countries and in Canada 59 .
The new lipoglycopeptide dalbavancin -FDA approved for acute bacterial skin and skin structure infections -has a high microbiological activity against staphylococci and enterococci. Moreover, dalbavancin has long half-life (up to 250 hours), which makes it a suitable option for a more rapid hospital discharge. However, a Phase II study which aimed to evaluate the effectiveness of dalbavancin in patients with blood stream infections or infective endocarditis was stopped early due to economic reasons (NCT03148756) and data are insufficient to support its use in this setting 60,61 .

Conclusion
There is a significant need for novel antibacterial drugs and this research and development efforts recently resulted in few new drugs or combination of drugs proposed for use into the clinic. There is a significant increase in the number of the new FDA approved drugs in the past 2 years compared to the previous years, since the number of antibacterial drugs or regimens in the past 2 years (9 antibacterial agents) is almost double the number of the ones from any 2 previous years, within the past 17 years.
The novel US FDA approved antibacterial agents in the last two years (2018-2019): plazomicin, eravacycline, sarecycline, omadacycline, rifamycin (2018) and imipenem, cilastatin and relebactam combination, pretomanid, lefamulin, cefiderocol (2019) are new players in the field of resistant bacteria treatment for specific indications. However, the number and efficiency of these new drugs is far from covering all the existing needs, to fully combat highly adaptive microorganisms. Thus, there is a real need and urgency to develop novel antibiotic strategies and drugs to overcome the bacterial resistance to antibiotics.
Through this review, we aim to further encourage the scientific community to continue the development of new therapeutic agents for targeting bacterial resistance. resistance in bacterial pathogens in metal and microplastic contaminated environments: an emerging health threat.