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Diabetes Watch

A Closer Look At A New Fluoroquinolone For Skin And Soft Tissue Infections

Diabetic foot ulcerations and infections (DFUs and DFIs) require a multidisciplinary approach with treatment including patient education, foot care (preventative care and risk stratification), glycemic control, debridement, vascular optimization and antibiotic therapy.

Diabetic extremity ulcerations develop in approximately 15 percent of patients and are a leading cause of hospitalization and amputation.1 Reportedly, one leg is amputated every 30 seconds worldwide due to a DFU.1 Specifically, chronic leg ulcers and recurrence of infection are serious issues with one study demonstrating 20 percent of 600 wounds had not healed after two years of treatment with two-thirds of patients experiencing recurrent episodes of ulceration.2 These wounds are often associated with medical consequences such as infection, which may be complicated by cellulitis, sepsis and the recurrence of polymicrobial contamination and antibiotic resistance.

Antimicrobial resistance among certain organisms has become one of the most crucial public health dilemmas of our time. Some lower extremity conditions, such as web space infections and recurrent cellulitis, that can become difficult to treat have contributed to this pressing issue. Current national guidelines endorse the use of a fluoroquinolone plus an anti-methicillin-resistant Staphyloccus aureus (MRSA) agent for lower extremity infections.3

What You Should Know About Delafloxacin

Approved by the Food and Drug Administration in 2017, delafloxacin (Baxdela®, Melinta Therapeutics) is a fluoroquinolone physicians can utilize for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by designated susceptible Gram positive and Gram negative bacteria, including Staphylococcus aureus (methicillin-resistant and methicillin-susceptible (MSSA) isolates) and Pseudomonas aeruginosa.4–6 Delafloxacin also shows activity against ciprofloxacin-resistant Gram positive bacteria. Several clinicians have suggested that, while not currently indicated, delafloxacin may be a useful as a single agent to treat DFIs, DFUs or decubitus ulcers if one suspects a polymicrobial infection.6,7

The chemical makeup of delafloxacin provides this fluoroquinolone with several antimicrobial advantages in comparison to older-class agents such as ciprofloxacin or levofloxacin (Levaquin, Janssen Pharmaceuticals). The absence of a specific protonatable substituent enables the molecule to have increased intracellular penetration and concentration with enhanced bactericidal activity under acidic conditions. The molecule persists and remains at a neutral pH in its ionic form within the bacterial membrane and is not transported in an extracellular manner. This results in an increased potency in comparison to previous fluoroquinolones while at the same time establishing a decreased adverse event profile.

The administration of the antibiotic is simple with oral dosing at 450 mg every 12 hours (450 mg PO BID) while intravenous (IV) dosing is 300 mg every 12 hours. There are no renal dosing adjustments for oral or intravenous delivery in patients with kidney impairment, but IV dosing is reduced with an estimated glomerular filtration rate (eGFR) of 15/29 mL/min/1.73m2 to 200 mg every 12 hours. PO/IV administration is not recommended in patients with end-stage renal disease (stage 5, eGFR <15 including hemodialysis). The antibiotic still carries the risks of previous fluoroquinolones such as tendonitis, tendon rupture, dysglycemia, C. difficile-associated diarrhea, peripheral neuropathy and central nervous system effects. However, these all appear to be decreased with delafloxacin with limited adverse effect findings to date although greater surveillance is necessary.4,7–8

Some other positive factors of the antibiotic include a lack of food-altering metabolism, no evidence of QTc prolongation, no drug-to-drug interactions due to CYP450 metabolism, and no hepatic impairment dose adjustments necessary.

While a PubMed search does not reveal any studies related to delafloxacin’s specific use in the diabetic population for pedal infections, researchers have postulated that delafloxacin is promising for the empirical treatment of DFIs.6–8

Patients with diabetes often have low immunity in addition to other compromising disorders such as renal disease, vascular disease, peripheral neuropathy and metabolic disorders. In this compromised state, DFIs result and persist due to a reduced chemotaxis, adhesion and phagocytosis of monocytes and neutrophils; and bacteria-friendly wound environments with high levels of sugars and proteins. Further reduced blood supply secondary to atherosclerosis creates an ischemic, acidic local environment.7 This constellation of factors allows an invasion of bacteria with difficulty in healing both tissue damage (e.g. cellulitis) and wounds in a timely fashion, potentiating drug resistance.9

Delafloxacin’s ability to remain bactericidal in these harsh, acidic environments and keep antimicrobial concentrations in peri-necrotic tissue above the minimum inhibitory concentration (MIC) are just two of its many advantages in these difficult to treat infections.7,8 The use of delafloxacin has also demonstrated high penetration into and sustained high concentrations within biofilms, showing a similar effectiveness as daptomycin (Cubicin, Merck) and vancomycin.4,8 Delafloxacin has the advantage of intravenous and oral treatment, making outpatient use when resistance is a factor a key place for this treatment.

Case Study: How Delafloxacin Helped Resolve An MRSA Infection

A 70-year-old man with diabetes saw the senior author for several years with recurrent cellulitis of bilateral lower extremities, cultured as MRSA, that had become resistant to ciprofloxacin and levofloxacin (see photos 1 and 2). Normally, this patient would present to the office and due to the failure of several rounds of outpatient oral antibiotics, he would subsequently need to be admitted for IV antibiotic delivery.

The patient most recently presented with bilateral lower extremity infections (see photo 1). He started on a 10-day course of oral delafloxacin (1 tab, 450-mg PO BID) and multilayer compression with an Unna boot, Kerlix gauze and Coban wrap. In just seven days, both of his leg infections had essentially resolved from any open, draining wound or frank signs of bacterial infection (see photo 2). These results were unlike any previous course of oral antibiotic that the patient had taken. After finishing the recommended antibiotic course, the patient has been infection-free for the last six months.

In Summary

If physicians can prevent rehospitalization of these immunocompromised patients and decrease the global financial health burden that these lower extremity infections bring by simply prescribing a certain medication, then it is worth a try. Newer antibiotics do not always mean better but if there is a situation when the caustic effects to a patient are decreased while concomitantly increasing the potency and benefit of treatment, we as physicians need to pay attention. Physicians should work closely with their antimicrobial stewardship committees, infectious disease and pharmacy physicians, and hospital administration to determine if they should add a medication such as this to the formulary.6

The use of delafloxacin may be beneficial in select patients with challenging infections in whom first-line therapy may be appropriate, in patients with recurrent MRSA ABSSSIs or those patients with DFIs who have failed other therapy (IV or oral).

Dr. Kumar is an associate at Neuhaus Foot and Ankle in Nashville, TN. She is board-certified by the American Board of Wound Management and is also a Fellow of the American Board of Podiatric Medicine. She serves on the Antimicrobial Stewardship Board and Infection Control Committee at TriStar Summit Hospital in Hermitage, TN. Dr. Kumar is part of the wound care team at the TriStar Summit Hospital Wound Care Center and is certified in hyperbaric oxygen therapy.

Dr. Hood is a fellowship-trained foot and ankle surgeon associate at Neuhaus Foot and Ankle in Nashville, TN. Follow him on Twitter at @crhoodjrdpm or check out his website www.footankleresource.com, which contains information on student/resident/new practitioner transitioning as well as links to academic and education resources found throughout the Internet.

Drs. Kumar and Hood have disclosed that they have no business or financial ties with any of the aforementioned pharmaceuticals discussed in this article. They have no disclosures associated with the content of this guest column and have no stock, equity, or consultant affiliations with Melinta Therapeutics. The views, thoughts and opinions expressed in the article belong solely to Drs. Kumar and Hood.

References
1.     American Diabetes Association. Consensus development conference on diabetic foot wound care. Diabetes Care. 1999;22(8):1354–60.
2.     Callam MJ, Harper DR, Dale JJ, Ruckley CV. Chronic ulcer of the leg: clinical history. Br Med J. 1987;294(May):1389–91.
3.     Mogle BT, Steele JM, Thomas SJ, Bohan KH, Kufel WD. Clinical review of delafloxacin: a novel anionic fluoroquinolone. J Antimocrobial Chemother. 2018;73(2):1439–51.
4.     Saravolatz LD, Stein GE. Delafloxacin: a new anti-methicillin-resistant staphylococcus aureus fluoroquinolone. Clin Infect Dis. 2018;68(6):1059–62.
5.     Melinta Therapeutics. Baxdela® (delafloxacin) - full prescribing information / msds. 2017. Available from: https://www.baxdela.com/docs/baxdela-prescribing-information.pdf
6.     Mitchell S, Humphries RM. New and novel agents targeting resistant gram-negative bacteria: a review for the clinical microbiologist. Clin Microbiol Newsl. 2018;40(18):147–55.
7.     Bassetti M, Pecori D, Cojutti P, et al. Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections. Expert Opin Drug Metab Toxicol [Internet]. 2017;13(11):1193–200.
8.     Candel FJ, Penuelas M. Delafloxacin: design, development and potential place in therapy. Drug Des Devel Ther. 2017;11:881–91.
9.     Liu L, Li Z, Liu X, Guo S, Guo L, Liu X. Bacterial distribution, changes of drug susceptibility and clinical characteristics in patients with diabetic foot infection. Exp Ther Med. 2018;16(4):3094–8.
10.     Zubair M, Ahmad J. Potential risk factors and outcomes of infection with multidrug resistance among diabetic patients having ulcers: 7 years study. Diabetes Metab Syndr Clin Res Rev. 2019;13(1):414–8.

Additional References
11.    Wu S. A guide to emerging antibiotics for multi-drug resistant bacteria. Podiatry Today. 2019;32(3):36-43.
12.    Swain D, Taub J, Anwar N. What you should know about six emerging antibiotics for diabetic foot infections. Podiatry Today. 2018;31(8): 12-15.

Diabetes Watch
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By Peninnah R. Kumar, DPM, AACFAS, CWSP, and Christopher R. Hood Jr., DPM, AACFAS
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