What You Should Know About Six Emerging Antibiotics For Diabetic Foot Infections

Contrary to popular belief, there are many new antibiotics that are currently under development and testing. With increased antibiotic resistance plaguing the health care world, it is now more vital than ever that physicians stay current on the newest treatment options available for resistant organisms.

For DPMs, this includes the antibiotics that may have a role in diabetic foot and leg infections to help with limb salvage. There are six emerging antibiotics that may be helpful in treating diabetic foot infections.

Plazomicin (Zemdri, Achaogen) was recently approved by the Food and Drug Administration (FDA) for urinary tract infections due to Enterobacteriaceae. It has an off-label use for diabetic foot infections. Plazomicin is in the aminoglycoside class and developed from sisomicin, a derivative of gentamicin. It mainly has activity against the Enterobacteriaceae family of microorganisms such as E. coli and K. pneumoniae.¹ The drug is bactericidal and binds to the 30S subunit of the bacterial ribosome, disrupting the translocation of protein synthesis and causing misreading of the genetic code by attaching to the 16S ribosomal RNA aminoacyl site.²

When designing the novel antibiotic, researchers took care to ensure appropriate modifications to the chemical structure for defense against aminoglycoside-modifying enzymes in carbapenem-resistant Enterobacteriaceae.¹ Aminoglycosides can cause side effects such as nephrotoxicity and ototoxicity in patients. In a previous study, researchers noted no nephrotoxicity or ototoxicity in phase 1 of testing for plazomicin. In the second phase of the study, the researchers noted mildly elevated creatinine levels in 5.2 percent of the patients being treated with plazomicin.¹ Adverse events that may have been associated with plazomicin treatment were mild vertigo in one patient and mild unilateral permanent tinnitus in one patient.

A study by Brazilian researchers demonstrated the minimal inhibitory concentrations (MICs) of plazomicin to be of lower values in comparison to the other aminoglycosides tested for Enterobacteriaceae.³ One of the most common microorganisms present in diabetic foot infection is Enterobacteriaceae. One should consider the use of plazomicin in regard to diabetic foot infection.⁴

What The Preliminary Research Findings Reveal About Vaborbactam

Vaborbactam (Vabomere, Melinta Therapeutics) is a beta-lactamase inhibitor, previously known as RPX7009, that belongs to the class of cyclic boronic acid antibiotics that act against carbapenem-resistant Enterobacteriaceae by specifically inhibiting the Klebsiella pneumoniae carbapenemase. The Ambler classification consists of four categories (A-D), all of which contain beta-lactamases of different genes. This antibiotic only suppresses beta-lactamase in Ambler class A.

Researchers found through measurements of MIC that vaborbactam is best in combination with meropenem when the antimicrobial activity increases by 64-fold.⁵ When one uses either vaborbactam or meropenem separately, the effect on the bacteria is not as potent.

In phase 1 of one of the studies conducted to assess the effect of vaborbactam-meropenem on complicated urinary tract infections, the only side effect was mild lethargy.⁶ Currently, vaborbactam-meropenem is in phase 3 clinical trials for carbapenem-resistant Enterobacteriaceae and urinary tract infections.¹ With this in mind, vaborbactam-meropenem may have utility in treating diabetic foot infections as Enterobacteriaceae can also be a factor in diabetic foot infections. Researchers have noted promising results in treating urinary tract infections and bacteremia caused by Enterobacteriaceae.^4,5,7

Assessing The Pros And Cons Of Cefiderocol

Cefiderocol (Cephem, Shionogi), known previously as S-649266, is part of the antibiotic class known as the siderophore cephalosporins. The third position on the side chain has a catechol moiety conjugated to the structure, enhancing its effect on microorganisms. This novel antibiotic has activity against Gram-negative bacteria and especially against Pseudomonas aeruginosa.

Cefiderocol takes advantage of the pathway of iron uptake to gain access inside the bacterium when physicians administer the drug. Bacteria will form a complex with iron binded to the siderophore and allow the complex to pass through the transporters.⁸

The safety and tolerability of this agent is currently under evaluation. After performing a multiple dose study in Japan, researchers reported the following adverse events: rash, a blood thyroid-stimulating hormone level increase, pyrexia, increase in aspartate aminotransferase level, increase in alanine aminotransferase level, blood in the urine, headache, blood urea level increase and decrease in blood thyroid-stimulating hormone level.⁹ Preclinical data has proven that cefiderocol works successfully against P. aeruginosa with an associated decrease in colony forming units.¹⁰ This novel antibiotic is necessary as diabetic foot infection microorganisms gain resistance to known treatment regimens. A Korean hospital is continuing to exclude antibiotics for treatment of P. aeruginosa infections as the majority of the antibiotics they have utilized have already lost the battle to antibiotic resistance.⁴

Could Fosfomycin Have ‘Novel Efficacy’ For DFIs?

Fosfomycin (Monurol, Allergan) is a phosphonic acid derivative class of antibiotic that exhibits bactericidal properties and is available in both oral and intravenous forms.¹¹ Researchers originally described and isolated the antibiotic from cultures of Streptomyces species in 1969.¹² The antibiotic was approved for use for uncomplicated urinary tract and gastrointestinal infections in the United States in 1997.¹²
Fosfomycin targets bacteria by inhibiting cell wall synthesis by preventing the production of building blocks of peptidoglycan.¹¹ Researchers have found that fosfomycin has novel efficacy in the treatment of diabetic foot infections due to its broad-spectrum approach to both Gram-positive and Gram-negative bacteria.¹³ Studies have also shown that fosfomycin has excellent penetration of inflamed and infected tissue, which is common in diabetic foot infections.¹³

In addition, with the increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infections in the diabetic population, intravenous fosfomycin has proven to be highly active against MRSA.¹⁴ Fosfomycin is also effective in treating Enterococcus, including vancomycin-resistant Enterococci and Pseudomonas. As a result, one can consider fosfomycin a powerful antibiotic in colonized diabetic foot wounds with multiple organisms.

Can Omadacycline Provide A Viable Alternative In The Face Of Increasing Antibiotic Resistance?

Omadacycline (Paratek Pharmaceuticals) is a first-in-class aminomethylcycline, a new generation of tetracyclines, available in both oral and intravenous forms.^15,16 Omadacycline is currently in phase III trials for acute bacterial skin infections.¹⁶ This antibiotic is bacteriostatic in nature as it inhibits protein synthesis by binding to the 30S ribosomal subunit.¹⁷

Due to increasing antibiotic resistance, current tetracyclines have become much less effective. Omadacycline is promising as it retains activity against these tetracycline-resistant bacterial strains. Researchers have found that omadacycline is effective in treating both Gram-positive and Gram-negative infections as well as anaerobic infections involving the skin, and has similar efficacy to tigecycline (Tygacil, Pfizer).¹⁸ Anaerobic infections are frequently polymicrobial in nature and result in abscess formation, which is common in the diabetic foot.  

In addition, researchers have found that omadacycline has activity against MRSA and vancomycin-resistant Enterococci (VRE).¹⁷ Due to its broad-spectrum efficacy, omadacycline will be a powerful part of the treatment plan in the treatment of diabetic foot infections.

A Closer Look At The Potential Of Delafloxacin

Delafloxacin (Baxdela, Melinta Therapeutics) is a new fluoroquinolone, which is available in both oral and intravenous form. The FDA has approved delafloxacin for serious skin infections.¹⁹ Fluoroquinolones function by inhibiting DNA topoisomerases, enzymes that are involved in winding and unwinding DNA, which result in breaks in the DNA and eventual cell death.¹¹

Delafloxacin is chemically distinct from prior fluoroquinolones due to the absence of a protonatable substituent, causing it to be weakly acidic. Due to this molecular difference, the result is increased intercellular penetration and bactericidal activity under acidic conditions.²⁰ This property makes delafloxacin unique and superior in the setting of major infection.

In addition, researchers have shown that delafloxacin is susceptible against MRSA and Pseudomonas, pathogens commonly associated with diabetic foot infections.²¹ A recent study compared delafloxacin with tigecycline in MRSA infections with the cure rate being greater than 90 percent in both.²¹ Studies have shown delafloxacin is capable of treating infection within bone and deep-seated abscesses due to its unique structure, allowing it to have a specific niche.²² Due to its wide spectrum of activity, delafloxacin is a promising option for the treatment of diabetic foot infections.^20,23

In Conclusion

By having knowledge of emerging antibiotics available for diabetic foot infections, physicians can provide other treatment options for their patients and possibly help prevent amputations in this high-risk population.

Dr. Swain is a board-certified wound specialist physician (CWSP) of the American Board of Wound Management, and a Diplomate of the American Board of Podiatric Medicine. He is the Medical Director of the St. Vincent’s Wound Care and Hyperbaric Center at St. Vincent’s Southside Hospital, and is in private practice in Jacksonville, FL.

Dr. Taub is a second-year resident with the St. Vincent’s Medical Center Podiatric Surgical Residency Program in Jacksonville, FL.

Dr. Anwar is a first-year resident with the St. Vincent’s Medical Center Podiatric Surgical Residency Program in Jacksonville, FL.

References

1.     Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence. 2017; 8(4):403-416.
2.     Drew R. UpToDate. Available at https://www-uptodate-com.dmu.idm.oclc.org/contents/aminoglycosides?search=plazomicin&source=search_result&selectedTitle=1~1&usage_type=default&display_rank=1 .
Accessed April 29, 2018.
3.     Martins AF, Bail L, Ito CAS, et al. Antimicrobial activity of plazomicin against Enterobacteriaceae-producing carbapenemases from 50 Brazilian medical centers. Diagn Microbiol Infect Dis. 2018; 90(3):228-232.
4.     Kwon KT, Armstrong DG. Microbiology and antimicrobial therapy for diabetic foot infections. Infect Chemother. 2018; 50(1):11-20.
5.     Castanheira M, Rhomberg PR, Flamm RK, Jones, RN. Effect of the beta-lactamase inhibitor vaborbactam combined with meropenem against serine carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2016; 60(9):5454-5458.
6.     Griffith DC, Loutit JS, Morgan EE, Durso S, Dudley MN. Phase 1 Study of the safety, tolerability, and pharmacokinetics of the beta-lactamase inhibitor vaborbactam (RPX7009) in healthy adult subjects. Antimicrob Agents Chemother. 2016; 60(10):6326-6332
7.     Letourneau AR. Combination beta-lactamase inhibitors, carbapenems and monobactams. UpToDate. Available at https://www.uptodate.com/contents/combination-beta-lactamase-inhibitors-carbapenems-and-monobactams . Published April 5, 2018.
8.     Ito A, Nishikawa T, Matsumoto S, Yoshizawa H, et al. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2016; 60(12):7396-7401.
9.     Saisho Y, Katsube T, White S, Fukase H, Shimada J. Pharmacokinetics, safety, and tolerability of cefiderocol, a novel siderophore cephalosporin for Gram-negative bacteria, in healthy subjects. Antimicrob Agents Chemother. 2018; 62(3):1-12
10.     Ghazi IM, Monogue ML, Tsuji M, Nicolau DP. Humanized exposures of cefiderocol, a siderophore cephalosporin, display sustained in vivo activity against siderophore-resistant Pseudomonas aeruginosa. Pharmacology. 2018; 101(5-6):269-275.
11.     Gallagher JC, MacDougall C. Antibiotics Simplified, Third Edition. Jones & Bartlett Learning, Burlington, MA, 2014.  
12.     Falagas ME, Giannopoulou KP, Kokolakis GN, Rafailidis PI. Fosfomycin: use beyond urinary tract and gastrointestinal infections. Clin Infect Dis. 2008; 46(7):1069-1077.
13.     Legat FJ, Maier A, Dittrich P, Zenahlik P, Kern T. Penetration of fosfomycin into inflammatory lesions in patients with cellulitis or diabetic foot syndrome. Antimicrob Agents Chemother. 2003; 47(1):371-374.
14.     Schintler M, Traunmuller F, Kreuzwirt G. High fosfomycin concentrations in bone and peripheral soft tissue in diabetic patients presenting with bacterial foot infection. J Antimicrob Chemother. 2009; 64(3):574-578.
15.     Wilcox M, Cure-Bolt N, Chitra S, Tzanis E, McGovern P. Efficacy and safety of omadacycline in patients with acute bacterial skin and skin structure infections and high body mass index or type 2 diabetes: a subgroup analysis from the OASIS trial. Presented at ID Week 2017, San Diego, CA.
16.     Villano S, Steenbergen J, Loh E. Omadacycline: development of a novel aminomethylcycline antibiotic for treating drug-resistant bacterial infections. Future Microbiology. 2016; 11(11):1421-1431.
17.     Pfaller M, Husband M, Shortridge D, Flamm R. Surveillance of omadacycline activity tested against clinical isolates from the United States and Europe as part of the 2016 SENTRY antimicrobial surveillance program. Antimicrob Agents Chemother. 2018;62(4)e02327.
18.     Stapert L, Wolfe C, Shinabarger D, Marra A, Pillar C. In vitro activities of omadacycline and comparators against anaerobic bacteria. Antimicrob Agents Chemother. 2018; 62(4):1-4.
19.     Hoover R, Alcorn H Jr, Lawrence L, et al. Pharmacokinetics of intravenous delafloxacin in patients with end stage renal disease. J Clin Pharmacol. 2018; 58(7):913–19.
20.     Abbas M, Paul M, Huttner A. New and improved? A review of novel antibiotics for Gram-positive bacteria. Clin Microbiol Infect. 2017; 23(10):697-703.
21.     Candel FJ, Penuelas M. Delafloxacin: design, development and potential place in therapy. Drug Design Devel Ther. 2017; 11:881-891.
22.     Jorgensen SC, Mercuro NJ, Davis SL, Rybak MJ. Delafloxacin: place in therapy and review of microbiologic, clinical and pharmacologic properties. Infect Dis Ther. 2018; 7(2):197–217.  
23.     O’Riordan W, McManus A, Teras J, Poromanski I. A comparison of the efficacy and safety of intravenous followed by oral delafloxacin with vancomycin plus aztreonam for the treatment of acute bacterial skin structure infections: a phase 3, multinational, double-blind randomized study. Clin Infect Dis. 2018; epub March 6.

For further reading, see “Top 10 Antibiotics For Managing Diabetic Foot Infections” in the August 2017 issue of Podiatry Today.