A Guide To Emerging Antibiotics For Multi-Drug Resistant Bacteria

The rise of bacteria that are resistant to multiple drugs highlights the urgency of developing new antibiotics to combat lower extremity infection. Accordingly, this author explores the potential of new pharmacological agents such as tedizolid, oritavancin, dalbavancin and delafloxacin, and discusses other agents in the pipeline.

Since the introduction of penicillin as the first true antibiotic in 1928, a plethora of antibiotics has become commercially available and has had a profound impact on life. Antibiotics are manufactured worldwide at an estimated scale of about 100,000 tons annually but the common use of antibiotics for farm animals, aquaculture and human therapy has led to increased strains of pathogens becoming antibiotic resistant.¹

Some pathogens have become resistant to multiple antibiotics and pharmaceutical agents, leading to the phenomenon of multidrug resistance. An example of such phenomenon is methicillin-resistant Staphylococcus aureus (MRSA). In addition to being resistant to methicillin, MRSA is usually also resistant to aminoglycosides, macrolides, tetracycline, chloramphenicol, lincosamides and disinfectants.¹

Multidrug resistance in bacteria occurs secondary to one of two mechanisms. One is by the accumulation of multiple resistant genes within a single bacterial cell. This accumulation generally occurs on resistance plasmids or transposons of genes with each coding for resistance to a specific drug agent.^1,2 Another mechanism is by the increased expression of genes that code for multidrug efflux pumps that essentially have the ability to extrude more than one drug type out of the bacterial cell.¹

Researchers reported the first case of MRSA in Great Britain in 1961 and in the U.S. in 1968.² Interestingly, vancomycin, an antibiotic that was first discovered in the 1950s but bypassed in favor of other antibiotics deemed equally or more efficacious and less toxic, was resurrected in the 1980s for the treatment of MRSA and pseudomembranous enterocolitis.³ This dramatic resurgence led to a 100-fold increase in the use of vancomycin over the next two decades and transferable resistance to vancomycin became fairly common with both MRSA and Enterococcus.⁴

In 2000, linezolid (Zyvox, Pfizer) became the first oxazolidinone approved by the Food and Drug Administration (FDA) for the management of both complicated and uncomplicated skin and skin structure infections, community-acquired pneumonia, nosocomial pneumonia and vancomycin-resistant Enterococcus faecium infections.⁵ Since linezolid’s release, however, there have been reports of MRSA strains resistant to linezolid due to the acquisition of a natural resistance gene known as chloramphenicol-florfenicol (cfr) resistance.^6,7 This imposed further challenges to the clinical management of infections, resulting in the development of novel antibiotics against multidrug resistant Gram-positive pathogens.

That said, there is a growing armamentarium of new, innovative pharmacological agents including tedizolid, oritavancin, dalbavancin and delafloxacin. Since the Food and Drug Administration (FDA) uses non-inferiority trials as criteria for drug approval, most of the available research compared these newer pharmacologic agents to either vancomycin or linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSIs).

What You Should Know About Tedizolid

Tedizolid phosphate (Sivextro, Merck & Co.) is a second-generation drug in the oxazolidinone class of antibiotics.⁵ It has activity against Gram positive organisms including methicillin-susceptible Staphylococcus aureus (MSSA), MRSA, Streptococcus pyogenes, Streptococcus agalactiae, vancomycin-resistant enterococci (VRE) and coagulase-negative staphylococci.⁸ Moreover, tedizolid has demonstrated activity against linezolid-resistant as well as vancomycin/daptomycin-resistant staphylococci.^8,9

Tedizolid received FDA approval in 2014 for the treatment of ABSSSIs in adults.¹⁰ This provides a newer oral alternative to linezolid for the treatment of MRSA infections. Tedizolid is a prodrug that is rapidly converted by plasma phosphatases into the active compound tedizolid and potentially has four- to 16-fold potency against MRSA in comparison to linezolid.^5,10,11 Tedizolid inhibits bacterial translation and protein synthesis by interacting with the bacterial 23S ribosome initiation complex and binding to the 50S subunit to prevent the formation of the 70S complex.^5,10

Unlike linezolid, tedizolid only requires once daily dosing. In two randomized controlled phase III trials (ESTABLISH-1 and ESTABLISH-2), 200 mg of tedizolid once daily for six days was non-inferior to 10 days of 600 mg of linezolid twice daily in the treatment of ABSSSIs.^8,12

Moreover, tedizolid appears to have a better safety profile with a reduced risk of myelosuppression.^5,8 It also differs from linezolid in the incidence of gastrointestinal and hematologic side effects, and appears to lack drug interactions with selective serotonin reuptake inhibitors.^5,8 Joseph and colleagues retrospectively analyzed the combined data from the ESTABLISH-1 and 2 trials, and found that over 40 percent of the total infections were in the lower extremity (foot, leg, thigh).¹³ The authors noted no difference in outcomes between lower extremity infections versus infections at other sites, and no difference in outcomes between tedizolid and linezolid.¹³ The results of current data suggest that tedizolid may be an effective new oral antibiotic agent for the treatment of ABSSSI with an improved safety profile in comparison to linezolid.

A Closer Look At The Potential Of Oritavancin

Oritavancin (Orbactiv, Melinta Therapeutics) is in the semisynthetic new-generation lipoglycopeptide class of antibiotics. It is indicated for the treatment of adults with ABSSSI caused by susceptible organisms, including MRSA, MSSA, Enterococcus faecalis (vancomycin-susceptible isolates only), and certain Streptococcus species.¹⁴

Oritavancin is a bactericidal agent with three mechanisms of action that result in concentration-dependent activity against relevant Gram-positive pathogens. Oritavancin has demonstrated bacterial membrane depolarization and permeabilization properties to facilitate its rapid bactericidal activity.¹⁵ Researchers have observed that this antibiotic inhibits transpeptidation, the other essential enzymatic step in peptidoglycan polymerization to reduce bacterial cell wall integrity.¹⁶ Moreover, oritavancin, through its unique structure, is capable of maintaining binding affinity for the modified peptidoglycan peptide termini of vancomycin-resistant organisms.^16,17

Oritavancin received FDA approval in 2014. The recommended dosage for the treatment of ABSSSI is 1,200 mg administered intravenously as a single infusion for over three hours. This is to minimize the risk of infusion-related reactions that resemble “red man syndrome” including flushing of the upper body, pruritus and/or rash. In two phase III, multicenter, double-blind, non-inferiority trials (SOLO I and SOLO II), researchers evaluated the efficacy and safety of a single 1,200-mg dose of oritavancin versus a seven- to 10-day course of vancomycin for the treatment of ABSSSI.^19,20 Results from both studies demonstrated that single-dose treatment of ortiavancin was non-inferior to twice daily treatment with vancomycin for treatment of ABSSSI.

Oritavancin is 90 percent protein bound, resulting in a prolonged half-life ranging from 200 to 300 hours, thereby facilitating the convenience of a single dose to complete a seven-day treatment duration.²¹ The body excretes oritavancin unchanged and no dose adjustment is required on the basis of age, hepatic function or renal function for patients with moderate renal/hepatic impairment.¹⁸ There is also no need for therapeutic drug monitoring.

It is important to note that phase III ABSSSI trials have reported a greater incidence of osteomyelitis in oritavancin-treated patients in comparison with vancomycin-treated patients.^19,20 Therefore, clinicians should monitor patients for signs and symptoms of osteomyelitis, and treat them accordingly if they suspect or diagnose osteomyelitis.¹⁴

Key Insights On The Use Of Dalbavancin

Dalbavancin (Dalvance, Allergan) is another semisynthetic second-generation lipoglycopeptide. It was engineered as an improved alternative to the naturally available glycopeptides such as vancomycin and teicoplanin. Like other glycopeptides, dalbavancin’s mechanism of action involves inhibiting bacterial cell wall biosynthesis by the formation of a complex with the C-terminal D-alanyl-D-alanine of growing peptidoglycan chains.²²

Dalbavancin has demonstrated four to eight times more potent bactericidal activity than vancomycin against many resistant Gram-positive organisms such as MRSA due to its ability to dimerise and anchor its lipophilic side chain in the bacterial membranes.^23,24 This is evidenced by dalbavancin having minimum inhibitory concentrations (MICs) consistently <0.125 µg/mL, which is much lower than most other anti-MRSA agents.²⁴ However, dalbavancin, like oritavancin, is not active against vancomycin-resistant Staphylococcus aureus.

Dalbavancin received FDA approval in 2014 for the treatment of ABSSSI with once-a-week dosing of 1,000 mg on day one followed by 500 mg a week later. Dalbavancin dosing does not need adjusting in patients receiving regularly scheduled hemodialysis and in patients with mild hepatic and renal impairment. For patients with severe renal impairment (creatine clearance <30mL/min) who are not receiving regularly scheduled hemodialysis, the recommended dose is either 1,125 mg IV as a single dose or 750 mg IV once followed by 375 mg IV a week later.

Dalbavancin has an extended terminal half-life of two weeks, related in part to it being approximately 95 percent protein bound.²⁴ This long half-life allows for a once-weekly dosing interval, bypassing the need for daily dosing.²⁵ Two double-blinded randomized multicenter trials (DISCOVER 1 and DISCOVER 2) compared once-weekly dalbavancin versus twice-daily vancomycin with the option to switch to oral linezolid.^26,27 The authors of both studies concluded that dalbavancin was non-inferior to vancomycin and linezolid for the treatment of ABSSI. While dalbavancin’s unique dosing regimen may appear ideal for conditions such as osteomyelitis that require long-term antibiotic treatment, robust clinical trials in this area are currently lacking. Future development efforts may focus on a single dose regimen as well as additional indications for dalbavancin.

What The Research Reveals About Delafloxacin

Delafloxacin (Baxdela, Melinta Therapeutics) is a novel dual-targeting anionic fluoroquinolone with in vitro activity against MRSA.²⁸ It received FDA approval for the treatment of ABSSSIs in 2017.

The fluoroquinolone class of antibiotics has not traditionally been among the first-line options for ABSSSI. Delafloxacin, however, is chemically distinct from currently marketed fluoroquinolones due to the absence of a protonatable substituent.²⁸ This provides a weakly acidic character to the molecule. The unique structural and chemical characteristics facilitates delafloxacin’s increased intracellular penetration and enhanced bactericidal potency under the low pH environments that are characteristic of infectious milieu.^28,29 This is in contrast to other zwitterionic fluoroquinolones that tend to lose antibacterial potency under acidic conditions.²⁸

The fluoroquinolone class of antibiotics acts by inhibiting two key enzymes, DNA gyrase and topoisomerase IV.³⁰ Both enzymes are essential for bacterial replication. Each specific fluoroquinolone antibiotic will differ in relative inhibitory potency with DNA gyrase as the preferential target among Gram-negative bacteria and topoisomerase IV as the more sensitive target for Gram-positive pathogens.^28,30 Delafloxacin has greater affinity for DNA gyrase in comparison with other fluoroquinolones.³¹ This affinity is attributable to delafloxacin having MICs that are consistently three- to fivefold lower than comparator fluoroquinolones against Gram-positive organisms.²⁸

Two phase III multicenter, randomized, double-blind, studies demonstrated the non-inferiority of delafloxacin to vancomycin plus aztreonam for the treatment of adult patients with ABSSSIs.^32,33 However, the two studies excluded patients with osteomyelitis, diabetic foot infections and necrotizing fasciitis.  

What Antibiotics Are In The Pipeline?   

There are several novel antimicrobial agents entering the long-dormant drug development pipeline. While these agents are at varying stages from newly discovered to close to FDA approval, they are generating excitement and hope as an increasing number of pathogens become resistant to currently available drugs worldwide.

Ceftobiprole. Ceftobiprole (Zevtera, Basilea Pharmaceutica) is part of a new generation of broad-spectrum parenteral cephalosporin active against MRSA. It inhibits bacterial cell wall synthesis by exhibiting greater binding affinity than other cephalosporins to penicillin-binding proteins (PBP2a) responsible for the methicillin resistance in staphylococci.³⁴ It has also demonstrated activity against vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus.³⁵ Ceftobiprole exhibits minimal plasma protein binding (16 percent) and the half-life of the drug is approximately three to four hours.

In a randomized controlled trial, Noel and colleagues showed the non-inferiority of ceftobiprole in comparison with vancomycin and ceftazidime for the treatment of complicated skin and skin structure infections.³⁶ A similar trial comparing ceftobiprole with vancomycin alone yielded similar outcomes.³⁷ Ceftobiprole is not currently approved for use in the United States but is marketed in Canada and 13 European countries.

Nemonoxacin. Nemonoxacin (Taigexyn, TaiGen Biotechnology) is a novel C-8-methoxy non-fluorinated quinolone.³⁸ It exhibits potent in vitro activity against Gram-positive bacteria, including MRSA and fluoroquinolone-resistant MRSA, Gram-negative bacteria and atypical pathogens. Nemonoxacin differs from fluoroquinolones in that it lacks the fluorine in the C6 position. The fluorine at C6 improves cell penetration and gyrase affinity.³⁸ Similar to other fluoroquinolones, nemonoxacin acts by inhibiting bacterial DNA gyrase and topoisomerase IV. It has a reduced propensity for resistance development as three different mutations need to occur in order for the bacteria to become resistant.³⁸ Nemonoxacin is available in both oral and intravenous formulations. Phase III studies of oral nemonoxacin for diabetic foot infection are currently underway.

Teixobactin. Naturally occurring antibiotics are widely dispersed throughout nature, where they play an important role in regulating microbial population of soil, water, sewage and compost.³⁹ In fact, penicillin, the first antibiotic, was obtained from a blue-green mold of the soil called Penicillium notatum.³⁹ Since that time, several hundred naturally produced antibiotics from the soil have been purified but only a few have been found to be safe for human use and adopted into medical practice. Given that uncultured bacteria make up 99 percent of all species in external environments, we were previously limited by available resources to culture most of the naturally occurring bacteria as they would not grow in laboratory conditions.⁴⁰ Recent technology has allowed us to screen and culture previously unculturable bacteria in external environments, resulting in a potentially potent source of new antibiotics.

One such example is teixobactin. Teixobactin is in a recently described new class of antibiotic that was discovered through a revolutionary method for bacterial culture. It is produced by a previously undescribed soil microorganism provisionally called Eleftheria terrae.⁴¹ Teixobactin was isolated with a new device called the isolation chip (iChip) that allows environmental bacterium to grow within its soil environment and for the antibiotic it produced to be isolated and subsequently identified.

Teixobactin is a cyclic depsipeptide, which was discovered in a screen of uncultured bacteria. It shows potent activity against all the tested Gram-positive bacteria and mycobacteria. It does not, however, have activity against Gram-negative organisms.⁴¹ Teixobactin has a novel mode of action and works by inhibiting peptidoglycan biosynthesis. Remarkably, despite extensive efforts, researchers have obtained no teixobactin-resistant Staphylococcus aureus or Mycobacterium tuberculosis bacterial strains.³⁵

Teixobactin is still at the early stages of development and there are no guarantees it will make it to market. NovoBiotic Pharmaceuticals has received two patents on the antibiotic. However, current work is underway to design and synthesize novel teixobactin analogues to improve antibiotic activity and efficacy.⁴² Given that there has been no new class of antibiotics discovered since 1987 for the treatment of systemic bacterial infections, the use of iChip technology to discover potentially new antibiotics is promising.

In Conclusion

Complicated skin and soft tissue infections secondary to multidrug resistant bacteria such as MRSA continue to be prevalent in health care settings and the community at large. These infections are often associated with longer hospital stays and longer duration of antibiotic use, and impose greater costs on the health care system. Newly developed antimicrobial agents with demonstrated efficacies via multiple prospective randomized phase III clinical trials are now approved and available in the United States.

An even more serious threat may be the emergence of Gram-negative pathogens that are resistant to essentially all of the currently available agents, notably those belonging to Pseudomonas aeruginosa and Acinetobacter baumanii. The discovery of new classes of antibiotics and synthesis of effective analogues using new technology is promising in our continued fight against bacterial resistance.

Dr. Wu is the Associate Dean of Research, a Professor in the Department of Podiatric Surgery and Applied Biomechanics, a Professor in the Center for Stem Cell and Regenerative Medicine, and the Director of the Center for Lower Extremity Ambulatory Research (CLEAR) for Dr. William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine and Science.

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