|Year : 2012 | Volume
| Issue : 11 | Page : 537-547
Newer antibacterials in therapy and clinical trial
Simi S Paknikar1, Sarala Narayana2
1 Consulting Medical Writer and Editor, India
2 Department of Pharmacology, Sri Devaraj Urs Medical College, Tamaka, Kolar, Karnataka, India
|Date of Web Publication||9-Nov-2012|
Simi S Paknikar
F-502, Nandi Woods, SOS Village Post, Yelenahalli, Begur Hobli, Off Bannerghatta Road, Bangalore- 560 076, Karnataka
Source of Support: None, Conflict of Interest: None
In order to deal with the rising problem of antibiotic resistance, newer antibacterials are being discovered and added to existing pool. Since the year 2000, however, only four new classes of antibacterials have been discovered. These include the oxazolidinones, glycolipopeptides, glycolipodepepsipeptide and pleuromutilins. Newer drugs were added to existing classes of antibiotics, such as streptogramins, quinolones, beta-lactam antibiotics, and macrolide-, tetracycline- and trimethoprim-related drugs. Most of the antibacterials are directed against resistant S. aureus infections, with very few against resistant gram-negative infections. The following article reviews the antibacterials approved by the FDA after the year 2000 as well as some of those in clinical trials. Data was obtained through a literature search via Pubmed and google as well as a detailed search of our library database.
Keywords: Antibiotic resistance, Latest antibacterials, New antibacterials
|How to cite this article:|
Paknikar SS, Narayana S. Newer antibacterials in therapy and clinical trial. North Am J Med Sci 2012;4:537-47
| Introduction|| |
The need for novel antibacterials has been greater than ever in the face of increasing resistance to the older ones. Three classes of drug-resistant bacteria are a major cause of concern- Methicillin -resistant Staphylococcus aureus (MRSA), multidrug-resistant (MDR) and pan-drug-resistant (PDR) gram-negative bacteria, which include strains of Acinetobacter baumannii, Escherichia More Details 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). 
This article reviews the antibacterials approved for clinical use by the FDA since the year 2000 and those in clinical trials, especially in the later phases. Information was obtained through a literature search via Pubmed and Google using keywords like 'newer antibiotics', 'newer antibacterials', 'antibacterials' and 'antibiotics'. The internet search was accompanied by a detailed search of our library database. Since the topic is extensive, we omitted results on antitubercular drugs.
| The Newer Antibacterials|| |
Antibacterials belonging to chemical classes introduced after the year 2000
Antibacterials belonging to chemical classes introduced after 2000 are described in [Table 1].
|Table 1: Antibacterials belonging to chemical classes introduced after 2000|
Click here to view
The oxazolidinones include:
In clinical use: Linezolid
In clinical trials: Radezolid, torezolid.
The development of another oxazolidinone PF-708093 was stopped after it entered Phase I clinical trials. 
The oxazolidinones are a new class of drugs effective against gram-positive bacteria including MRSA, vancomycin-resistant enterococci (VRE) and Streptococcus pneumoniae. Besides, they are also effective against Mycobacterium tuberculosis and Nocardia. 
Linezolid is among the first antibacterials to be approved for clinical use this millennium. It is indicated for the treatment of vancomycin-resistant Enterococcus faecium infections, nosocomial and community-acquired pneumonia, as well as skin and soft tissue infections.
Linezolid is bacteriostatic against drug-resistant organisms like MRSA and VRE. Minimum inhibitory concentration (MIC) is less than 4 μg/ml for strains of S. aureus. Linezolid inhibits bacterial protein synthesis at an early stage and inhibits the formation of a functional initiation complex. Mutations in the peptidyl transferase centre of the rRNA result in resistance to linezolid. 
Linezolid is associated with serious adverse effects like bone marrow suppression, peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome (when used with selective serotonin uptake inhibitors). It also shows mild monoamine oxidase (MAO) inhibitory activity. 
Radezolid has completed phase II clinical trials in complicated skin and soft tissue infections and community-acquired pneumonia with positive results. It differs from linezolid by the presence of a biaryl spacer and a heteroaryl side chain. This chemical modification increases ionization, makes the molecule hydrophilic at physiological pH and confers a dibasic character to it, thus improving the antimicrobial spectrum to include linezolid-resistant strains.  In vitro studies indicate that radezolid is 10-times more potent than linezolid due to higher intrinsic activity and cellular accumulation.  Thus, this drug could be particularly useful in persistent intracellular infections.
Torezolid is the active moiety of torezolid phosphate, a second-generation oral oxazolidinone. Studies claim that it shows a 4-to 16-times greater potency than linezolid against gram-positive species including MRSA. Unlike linezolid, it has been found to be bactericidal in an animal model  and is active against linezolid-resistant strains of S. aureus in vitro. MRSA and MSSA strains also show 16 times lower frequency of spontaneous resistance as compared to strains exposed to linezolid. Torezolid has undergone phase II clinical trials for complicated skin and soft tissue infections with good efficacy and an acceptable side effect profile.  Its mean half-life of 8-11.1 h is approximately two-fold longer than that of linezolid, thus allowing once-daily dosing. 
In clinical use: Daptomycin, telavancin
Under clinical trials: Oritavancin.
Dalbavancin, a glycolipopeptide that requires only once-a-week dosing,  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. 
Daptomycin is a cyclic lipopeptide with a decanoyl side-chain approved by the FDA in the year 2003 for the treatment of complicated skin and skin-structure infections caused by methicillin-susceptible or methicillin-resistant S. aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis and Enterococcus faecalis (vancomycin-susceptible only).  It has also been approved for use in bacteremia and endocarditis  caused by MSSA or MRSA. It is inactivated by surfactant and is therefore contraindicated in pneumonia. 
Daptomycin exhibits rapid bactericidal activity against most gram-positive organisms including multiple-antibiotic resistant strains. Approximately 90% strains of staphylococci and streptococci are inhibited at concentrations of 0.25-0.5 μg/ml; similarly, the concentrations that inhibit 90% of E. faecalis and E. faecium are 0.5-1 and 2-4 μg/ml, respectively. The MICs for vancomycin-resistant strains tend to be higher than for vancomycin-susceptible organisms. 
Daptomycin 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. 
Telavancin was approved for use in 2009 for complicated skin and soft tissue infections caused by gram-positive bacteria including MRSA strains. In vitro activity against some vancomycin-resistant gram-positive organisms has been observed. 
Telavancin exhibits a dual mechanism of action - It inhibits peptidoglycan chain formation through blockage of both, transpeptidation and transglycosylation during cell wall formation. It also dissipates membrane potential of the bacterial cell membrane causing an increase in permeability.
Adverse effects of telavancin include 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. 
Oritavancin is a lipoglycopeptide active against MRSA as well as VRE. It shows rapid bactericidal activity with a concentration-dependent post-antibiotic effect.  It inhibits transglycosylation as well as transpeptidation during peptidoglycan synthesis. It also blocks utilization of D-Ala-D-Ala or D-Ala-D-Lac containing PG precursors.  Currently, the FDA has accepted its New Drug Application (NDA) for standard review.
Oritavancin has a long half-life and undergoes mainly hepatic elimination, thus it may not require much dosage adjustment in renal failure patients, unlike the other lipoglycopeptides. 
In clinical trials: Ramoplanin.
Ramoplanin is a glycolipodepepsipeptide undergoing phase III clinical trials for use in Clostridium-difficile associated diarrhoea. Since it is effective only when administered orally and is not absorbed systemically, it is useful in local gastrointestinal infections.
Ramoplanin inhibits cell wall synthesis by inhibiting peptidoglycan formation. Unlike glycopeptides, it does not complex with the D-Ala-D-Ala sequence of cell wall precursors to inhibit cell wall synthesis. 
The pleuromutilins include:
In clinical use: Retapamulin
In clinical trials: BC-3781.
Tiamulin and valnemulin are used in veterinary medicine. BC-3205 and BC-7013 are in early phases of clinical trials.
Retapamulin is the first pleuromutilin that was approved in 2007 for topical use in the treatment of uncomplicated superficial skin infections.
Retapamulin exerts its antibacterial action by inhibiting protein synthesis. MIC90 value of retapamulin in in vitro studies was 0.12 g/ml against S. aureus, including mupirocin-resistant strains. Retapamulin appears to be approximately 1000 times as potent as mupirocin or fusidic acid against Streptococcus pyogenes.
Indications for retapamulin may increase in the future since it is effective against many common skin pathogens and has low potential for development of bacterial resistance. Side effects include pruritus and allergic contact dermatitis. 
BC-3781 is the first pleuromutilin antibacterial being developed for systemic use. It has recently completed Phase II trials and is 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. 
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 and listed in [Table 2].
Newer streptogramins are:
In clinical trials: NXL 103.
Virginamycin is a streptogramin used in fuel and ethanol industry, and in agriculture. Though not available in the United States, pristinamycin (or pristinamycine) is used in France, Belgium and some European countries
NXL-103 is a novel, orally administered streptogramin that has undergone Phase II trials. It contains linopristin and flopristin in a 30:70 ratio.
NXL-103 is 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 community-acquired pneumonia, community-acquired or nosocomial MRSA and VRE infections, and complicated skin and soft tissue infections. It has been shown to be up to 4 times more potent than quinupristin/dalfopristin in in vitro tests. Adverse effects in Phase I and Phase II clinical trials include vomiting, orthostatic hypotension, nausea, dizziness, headache, loose stools, and abdominal pain. Some abnormalities in liver enzymes have also been noted. 
The newer quinolones include:
In clinical use: Gemifloxacin, besifloxacin
In clinical trials: Nemonoxacin, finafloxacin, JNJ-Q2, delafloxacin, prulifloxacin, zabofloxacin.
Many of the new fluoroquinolones have anti-pseudomonal activity and additional anti-MRSA activity. 
Among the newer quinolones, 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 after it entered Phase I clinical trials due to prolongation of QT interval. The development of DC-159a and DX-619 was discontinued after Phase I trials. WCK 771, the arginine salt of S-(−)-nadifloxacin, is under clinical trials in India, though it is not yet being tested in the United States. Sitafloxacin is a new fluoroquinolone currently marketed in Japan.
Gemifloxacin is an oral fluoroquinolone approved in 2003 for treatment of acute bacterial exacerbation of chronic bronchitis and mild-to-moderate community-acquired pneumonia.
Gemifloxacin shows enhanced activity against gram-positive bacteria.  Its good potency against Strep pneumoniae appears to be due to high affinity for DNA gyrase and topoisomerase IV. Its activity against gram-positive organisms appears to be better than that of moxifloxacin, but its higher protein binding and lower serum levels result in similar activity. However, it has poor activity against methicillin-resistant strains.
Gemifloxacin also shows good activity against fluoroquinolone-resistant strains including fluoroquinolone-resistant H. influenzae.  It appears to be more active than ciprofloxacin against Chlamydia pneumoniae and Mycoplasma pneumoniae, but less active against Pseudomonas aeruginosa.
High concentrations are achieved in the respiratory tract after oral administration, making it an ideal drug for the treatment of respiratory tract infections. 
Besifloxacin was approved in 2009 as an ophthalmic suspension to treat bacterial conjunctivitis. Other formulations of the drug have not been developed to prevent indiscriminate use and thereby increase the chances of resistance to the drug.
Besifloxacin has clinical efficacy similar to moxifloxacin. It inhibits both DNA gyrase and topoisomerase IV and thus potentially reduces the chances for the development of resistance.
Besifloxacin is administered as eye drops 3 times a day. Its frequency of administration is similar to moxifloxacin and less than other fluoroquinolones, thus possibly increasing compliance. The duration between doses can vary between 4 and 12 hours, thus increasing flexibility of treatment. 
Quinolones undergoing clinical trials
Nemonoxacin is a nonfluorinated quinolone that has completed phase II clinical trials in community-acquired pneumonia and diabetic foot infections.  It shows good activity against a variety of gram-positive and negative organisms including MRSA, VRE and other multi-drug-resistant organisms. 
Finafloxacin has proven activity against MRSA, VRE and other drug-resistant strains as well as anaerobes. Oral and IV formulations of finafloxacin are undergoing phase II clinical trials. Currently, it appears to be safe without prolongation of QT interval and other serious side effects associated with fluoroquinolones. High tissue levels are achieved even in acidic environments of pus, urine and secretions from infected tissues.  Its once-a-day administration makes it an attractive drug. Currently, it is being tested for urinary tract infections and H pylori infections.
JNJ-Q2, a novel ﬂuorinated 4-quinolone, is undergoing phase II clinical trials with positive results in acute bacterial skin and soft tissue infections. Most adverse effects appear to be mild in preliminary studies. 
Delafloxacin is a new fluoroquinolone that shows good activity against gram-positive organisms compared to earlier quinolones, including MRSA strains. It also covers gram-negative organisms and anaerobes including resistant strains. It is effective in acidic environments. It has been developed as an oral and IV formulation and is being evaluated in complicated skin and soft tissue infections, community-acquired pneumonia and bronchitis. 
Among the other quinolones being evaluated, prulifloxacin has undergone limited studies and has the potential to be used in acute exacerbation of chronic bronchitis.  Zabofloxacin is undergoing phase II clinical trials for oral treatment of community-acquired pneumonia. 
Newer beta-lactam antibacterials
The newer beta-lactam antibacterials include:
In clinical use
In clinical trials
- Cephalosporins: Cefditoren pivoxil, ceftaroline
- Carbapenems: Ertapenem and doripenem. Biapenem is approved in some European countries but not in the United States.
Faropenem medoxomil was developed as intended treatment for community-acquired pneumonia and other respiratory tract infections. It underwent up to Phase III clinical trials. However, the development of the drug stopped after FDA issued a non-approvable letter in 2006 and requested additional clinical studies to demonstrate superiority. The development of another carbapenem, tomopenem was stopped due to unspecified reasons. 
- Cephalosporin: Ceftobiprole
- Carbapenems: Razupenem, sulopenem, ME 1036
Newer beta-lactam antibacterials in clinical use
Cefditoren pivoxil, a prodrug that releases cefditoren, is an oral cephalosporin approved by the FDA for clinical use in 2001. Cefditoren is a third-generation oral cephalosporin with good activity against certain respiratory tract pathogens, namely S. pneumoniae, H. influenzae and M. catarrhalis, including some β-lactamase producing strains.  Cefditoren pivoxil is also effective against Staphylococcus aureus (but not MRSA strains) and Streptococcus pyogenes (penicillin-susceptible strains only). MIC90 values for cefditoren against MSSA ranged from 0.5 to 1 mg/L, and were similar to those for cefuroxime and cefdinir, but lower than those for cefpodoxime, cefaclor, and cefixime. 
Cefditoren pivoxil is 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. 
Ceftaroline is the newest cephalosporin with anti-MRSA activity that obtained FDA approval in October 2010. It is used in the treatment of acute bacterial skin and skin-structure infections, and community-acquired bacterial pneumonia.
Ceftaroline is active against MSSA as well as MRSA isolates with MIC90 values of 0.25 and 1 mg/L, respectively. The low MIC values are indicative of ceftaroline's high affinity for penicillin-binding proteins. Ceftaroline is also effective against Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus pneumoniae, gram-negative bacteria like ceftazidime-susceptible E. coli and Klebsiella pneumoniae, and β-lactamase-positive and negative Haemophilus influenzae.
Ceftaroline, available as ceftaroline fosamil, is administered intravenously; dosage adjustment is required in renal failure. 
Ertapenem is a 1-β-methyl carbapenem approved for use by the FDA in the year 2001. It is effective against gram-positive and negative aerobic as well as anaerobic bacteria excluding the nonfermenters, MRSA and drug-resistant enterococci. It appears to be effective against most resistant enterobacteriaceae producing ESBLs and/or AmpC-type β-lactamases.  MIC90 values in in vitro studies for most species of Enterobacteriaceae were <1 mg/L, significantly lower than those of imipenem. MIC90s for most Bacteroides fragilis group isolates ranged from 1 to 4 mg/L, and from 0.06 mg/L for Clostridium perfringens to 4 mg/L for Clostridium clostridioforme. 
Since ertapenem has limited in vitro activity against P. aeruginosa and Acinetobacter species, it is more suitable for the empiric treatment of serious infections acquired in the community than those acquired nosocomially. Ertapenem is also recommended for prophylaxis of surgical-site infection following elective colorectal surgery. Unlike imipenem, ertapenem does not require co-administration with cilastin.
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; MICs for doripenem against extended-spectrum β-lactamase or AmpC producers are less than 1 μg/ mL, and between the ranges of 8-64 μg/mL against KPC-producing or metallo-β-lactamase-producing organisms.
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. 
Beta-lactam antibacterials in clinical trials
Ceftobiprole is an intravenous fourth-generation cephalosporin being developed for community-acquired pneumonia, skin and soft-tissue infections due to MRSA, and nosocomial pneumonia due to suspected or proven MRSA, including ventilator-associated pneumonia. 
Ceftobiprole has been submitted as a new drug application (NDA) to the FDA and has already been approved for use in some countries. It has limited activity against anaerobes and is not effective against extended spectrum β-lactamase, serine carbapenemases and metallo-β-lactamases producing species.  The prodrug ceftobiprole medocaril is currently formulated as an intravenous preparation.
Ceftobiprole facilitates a conformational change in penicillin-binding protein PBP2a, allowing the formation of a stable acyl-enzyme complex. It also has affinity to other staphylococcal binding proteins such as PBP1a, PBP1b, PBP2x, PBP2a, PBP2b and PBP3; this property is responsible for the high activity of ceftobiprole against staphylococci. It also binds to PBPs of other organisms such as S. pneumoniae, E coli and Pseudomonas aeruginosa with high affinity.
Adverse effects reported include a caramel-like taste disturbance, nausea, vomiting, headache and mild-to-moderate increase in liver enzymes. 
Among the carbapenems in clinical trials, razupenem is a novel β-methyl carbapenem that has completed Phase II clinical trials in complicated skin and soft-tissue infections. It is active against methicillin-resistant staphylococci and vancomycin-resistant enterococci, including Enterococcus faecalis but not Enterococcus faecium.  It also shows some activity against Enterobacteriaceae. 
Sulopenem shows good activity against gram-positive and gram-negative organisms and anaerobes except Pseudomonas aeruginosa. It is currently undergoing Phase II clinical trials in skin and soft-tissues infections. It is also being tested for use in community-acquired pneumonia. 
ME 1036 is an intravenous carbapenem in early clinical trials. 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. 
Newer macrolides and ketolides
Newer macrolides and ketolides include:
In clinical use: Fidaxomicin, telithromycin
In clinical trials: EDP-420, ketolides including cethromycin, solithromycin (CEM-101), PF-04287881.
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 is probably the latest antibacterial approved for use in May 2011. It is indicated in Clostridium difficile-associated diarrhoea. MIC50 and MIC90 values for C. difficile range from ≤0.016 to 0.25 μg/ml and 0.125 to 0.5 μg/ml, respectively. 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. Thus, it may be a preferred drug in cases of recurrence. 
Fidaxomicin exerts its bactericidal effect by 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 is the first ketolide in the market approved for use in 2004 for the treatment of mild-to-moderate community-acquired pneumonia caused by Streptococcus pneumoniae (including MDR isolates), Haemophilus influenzae, Moraxella More Details catarrhalis, Chlamydophila pneumoniae or Mycoplasma pneumoniae. 
Telithromycin is effective against erythromycin-resistant pneumococci. This is because of its enhanced binding to domain II of rRNA. MIC values for pneumococci vary from of 0.008 μg/mL to 0.015 μg/mL. 
Telithromycin was initially also indicated for the treatment of acute bacterial sinusitis and acute exacerbation of chronic bronchitis. However, it was withdrawn for these indications in 2007 due to its ability to cause serious adverse effects. Post-marketing surveillance revealed that telithromycin was associated with hepatotoxicity, exacerbation of myasthenia gravis, visual disturbances, and loss of consciousness. Its hepatotoxic potential resulted in narrowing of its indications to the treatment of mild-to-moderate community-acquired pneumonia only. 
Newer macrolides and ketolides undergoing clinical trials
EDP-420 is the first bridged bicyclic macrolide currently undergoing Phase II studies for the treatment of community-acquired pneumonia. It has shown good activity against respiratory tract pathogens including some drug-resistant strains. It also appears to show some activity against Mycobacterium avium. It has a long half-life that may permit less frequent dosage and for shorter periods. 
Cethromycin is a new ketolide that has been submitted as a New Drug Application for the treatment of mild-to-moderate pneumonia. It has completed phase III studies with positive results.
Cethromycin is highly active against S. pneumoniae, including drug-resistant strains. It also shows some activity against gram-negative organisms including Moraxella cattarhalis, Haemophilus influenzae and atypical pathogens.
Unlike telithromycin, cethromycin does not appear to be hepatotoxic in clinical trials. 
Solithromycin is a new fluoroketolide entering Phase II clinical trials for community-acquired pneumonia. It inhibits synthesis of bacterial ribosomal protein in a number of gram-positive as well as negative bacteria, including resistant strains. 
Newer tetracycline-related antibacterials
Newer antibacterials related to tetracyclines include:
In clinical use: Tigecycline
In clinical trials: PTK-0796.
Tigecycline is the glycylcycline and is a structural derivative of minocycline.  It was 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. It 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. 
PTK-0796, a first-in-class aminomethylcycline, is being developed as a once-daily treatment for MRSA, VRE, and some resistant gram-negative pathogens, including A. baumannii. It has entered Phase III trials for the use in complicated skin and soft-tissue infections.
PTK-0796 shows activity against gram-positive and gram-negative bacteria as well as atypical and anaerobic bacteria, including resistant strains such as MRSA, VRE and gram-negatives producing ESBL.  The oral form may enable people to continue the same treatment at home following discharge from the hospital.
Newer trimethoprim-related drug
In clinical trials: Iclaprim.
Iclaprim has undergone Phase III trials and has 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.
Iclaprim shows good activity against 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. 
| Conclusions|| |
Misuse of the older antibacterials has resulted in the problem of resistance that we face today. Unfortunately, the process of discovering a new antibacterial is a lengthy one. Only four new classes of antibacterials have been discovered in the last 11 years. The drugs in the pipeline are also not an extensive list. In addition, a number of drugs are discontinued during development. Though newer antibacterials are the need of the hour, it is also necessary to implement policies restricting their use. They should be available for use only for the specific conditions they are developed for. Their use in trivial infections and topical application should be avoided. Regulatory bodies can make it mandatory that these drugs should be available only in tertiary care hospital, thus preventing their rampant use and over-the-counter utility.
Most of the newly approved antibacterials are aimed to treat resistant gram-positive infections like those caused by MRSA and VRE. Research also needs to be directed towards other serious infections like those caused by resistant gram-negative bacteria and anaerobes.
Attempts have also been made during the discovery process to improve the pharmacokinetic properties of the newer antibacterial drugs. This should help to improve patient acceptability of the drugs and ensure that the patients complete the entire course, again to reduce the possibility of developing resistance.
The list of antibacterials likely to come out in the market in the next few years is short. An advice to use these drugs judiciously only in situations that they are specifically indicated for should accompany the medications. They should be administered under careful supervision to ensure that they do not suffer the same fate of their predecessors.
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[Table 1], [Table 2]
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