A Review of Novel Drugs for the Treatment of Skin and Soft Tissue Infections in the Foot and Ankle

Podiatric physicians have a variety of antibiotic options available for the treatment of skin and soft tissue infections related to the foot and ankle. The increasing prevalence of antibiotic-resistant strains has made it necessary to educate physicians on new antibiotics for these infections. Until recently, there has been a paucity of literature concerning newly available antibiotic therapies, especially within the foot and ankle literature.^1,2 In this piece, we will review and summarize the current state of knowledge on new antibiotics and provide a comprehensive review of the latest antibiotics for skin and soft tissue infections in the foot and ankle.

Specific antibiotic targeting is the cornerstone of infection control. One should only use empiric broad-spectrum antibiotics until cultures, specificities, and sensitivities are known. This makes accurate and effective treatment complicated, and increased mortality has been associated with undertreated and overtreated infection groups.³ In certain applicable cases, one may choose to omit empiric therapy until cultures return. However, a culture may not be appropriate for all situations.^4,5 Superficial swab cultures taken in the absence of a deep wound, bone, or drainage may only yield normal, nonpathological skin flora.

In a nonculturable wound, more invasive culture methodologies like tissue and bone biopsies can be considered. However, clinical judgment is of the utmost importance. Considerations of previous infections and resistance, presenting symptomatology, and medical comorbidities must be included in treatment decision-making. Appropriate outpatient antibiotic regimens can reduce healthcare-associated costs, complications, and increase patient satisfaction.^3,5

We focus the following section on important new and emerging antibiotic therapies as an update to those previously described in podiatric literature.^6–8

A Guide to Emerging Antibiotics

Omadacycline (Nuzyra, Paratek). Omadacycline is a tetracycline antibiotic approved by the Food and Drug Administration (FDA) for acute bacterial skin and skin structure infections (ABSSSI). This includes gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) (in vitro studies), and gram-negative bacteria. Omadacycline’s mechanism of action is via binding to the 30s ribosomes of bacteria inhibiting protein synthesis. Omadacycline is available orally or intravenously.⁹

Omadacycline can be a viable option for the treatment of the following ABSSSI and lower limb diabetic foot infections:⁹
Enterococcus faecalis
Staphylococcus aureus (methicillin-susceptible and -resistant isolates)
Staphylococcus lugdunensis
Streptococcus anginosus group
Streptococcus pyogenes
Enterobacter cloacae
Klebsiella pneumoniae

Studies looking at omadacycline efficacy found that omadacycline concentrations present in the interstitial space of soft tissue in both patients with diabetic foot infections and in healthy patients.¹⁰ The total plasma concentrations in both groups were also found to be similar.¹⁰

Tedizolid (Sivextro, Merck). Tedizolid is an oxazolidinone approved by the FDA for ABSSSI caused by gram-positive bacteria including MRSA.¹¹ Studies have also shown tedizolid to display activity against anaerobes typically implicated in diabetic foot infection such as Bacteroides fragilis as well as isolates resistant to imipenem, piperacillin-tazobactam, and metronidazole.¹²

Acute bacterial skin and skin structure infections coverage:
Gram-positive:¹²
Staphylococcus aureus (methicillin-susceptible and -resistant isolates)
Streptococcus agalactiae
Streptococcus pyogenes
Streptococcus anginosus group
Enterococcus faecalis

Tedizolid’s mechanism of action involves binding to the 50s subunit of the bacterial ribosome resulting in the inhibition of protein synthesis. Tedizolid is shown to be a bacteriostatic agent.¹³

In studies comparing tedizolid efficacy in patients with diabetic foot infection and healthy patients, tedizolid’s penetration into the interstitial extracellular fluid of lower limb soft tissue was not statistically different between the 2 groups.¹¹ Tissue concentrations were similar to free plasma concentrations for both groups.

Ceftaroline (Teflaro, AbbVie). Ceftaroline is a fifth-generation cephalosporin indicated in patients for the treatment of ABSSSI including gram-positive bacteria such as MRSA. In vivo studies have shown ceftaroline to cover gram-negative bacteria.¹⁴ Its mechanism of action involves the disruption of peptidoglycan cell wall synthesis. It is considered a bactericidal agent.¹⁵

Compared to daptomycin, ceftaroline shows lower admission rates and mortality in diabetic foot infections.¹⁶ Ceftaroline has also been shown to improve mortality rates and decrease the duration of bacteremia as combination therapy compared to monotherapy alone for MRSA bacteremia.¹⁷

Acute bacterial skin and skin structure infections coverage:¹⁵
Gram positive:
Staphylococcus aureus (methicillin-susceptible and -resistant isolates)
Streptococcus pyogenes
Streptococcus agalactiae
Gram negative:
Escherichia coli
Klebsiella pneumoniae
Klebsiella oxytoca

Oritavancin (Orbactiv and Kimyrsa, Melinta Therapeutics). Orbactiv and Kimyrsa are different formulations of the same lipoglycopeptide antibiotic Oritavancin. Oritavancin is indicated for treating ABSSSI caused by several gram-positive bacteria including MRSA. Research has found oritavancin to be noninferior to vancomycin for the treatment of gram-positive ABSSSI.¹⁸

Acute bacterial skin and skin structure infections coverage:¹⁸
Gram positive:
Staphylococcus aureus (methicillin-susceptible and -resistant isolates)
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus dysgalactiae
Streptococcus anginosus group
Enterococcus faecalis (vancomycin susceptible isolates)

Oritavancin’s mechanisms of action include inhibition of cell wall polymerization, inhibition of transpeptidation required for cell wall synthesis, and cell membrane disruption.¹⁹ Oritavancin does not require renal dosing in mild and moderate cases of insufficiency, but research has shown it to exert weak inhibitory activity towards cytochrome P450. As a result, oritavancin is contraindicated in patients receiving a heparin drip as it can affect lab value monitoring by falsely increasing coagulation studies. Oritavancin’s efficacy towards osteomyelitis is uncertain, but recent literature has shown favorable results.^19,20

Dalbavancin (Dalvance, AbbVie). Dalbavancin is a lipoglycopeptide antibiotic FDA approved for the treatment of ABSSSI caused by several gram-positive bacteria including MRSA. Dalbavancin’s mechanism of action involves interference with cell wall synthesis to prevent peptidoglycan cross-linking.²¹ Dalbavancin is bactericidal in vitro against S aureus and S pyogenes.²²

Acute bacterial skin and skin structure infections coverage:²²
Gram-positive:
Staphylococcus aureus (methicillin-susceptible and -resistant isolates)
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus dysgalactiae
Streptococcus anginosus group
Enterococcus faecalis (vancomycin susceptible isolates)

Although off-label, dalbavancin has been shown to display activity against challenging infections like diabetic osteomyelitis and prosthetic joint infections.^23–25 In studies comparing the efficacy of dalbavancin for the treatment of osteomyelitis, dalbavancin was as efficacious as the standard of care with the core advantage of once-a-week dosage.²⁶

Delafloxacin (Baxdela, Melinta Therapeutics). Delafloxacin is a fluoroquinolone antibiotic that is indicated for the treatment of ABSSSI and community-acquired bacterial pneumonia (CABP).²⁷ This medication covers gram-positive bacteria including MRSA and gram-negative organisms such as Pseudomonas.

Acute bacterial skin and skin structure infections coverage:²⁷
Gram-positive:
Staphylococcus aureus (methicillin-susceptible and -resistant isolates)
Streptococcus haemolyticus
Streptococcus lugdunensis
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus anginosus group
Enterococcus faecalis (vancomycin susceptible isolates)

Gram-negative:
Esherichia coli
Klebsiella pneumoniae
Enterobacter cloacae
Pseudomonas aeruginosa

Delafloxacin’s mechanism of action is through the inhibition of topoisomerase IV and DNA gyrase. Delafloxacin has been shown to be a highly effective antibacterial option, as seen in a study that found cure rates to be significantly better with delafloxacin versus vancomycin.²⁸ The difference was especially significant in patients with obesity. Researchers also found the percentage decrease in total erythema area was significantly greater with delafloxacin versus vancomycin at the time of follow-up. Lastly there was no difference in the total eradication of bacteria among the treatment groups.²⁸ Through various studies, delafloxacin has been shown to have good activity against a broad spectrum of microorganisms, including those resistant to fluoroquinolones as well as MRSA.²⁹ The pharmacokinetic properties seen as well as its excellent activity in acidic environments make delafloxacin an excellent alternative in soft tissue skin infections, especially those involving the diabetic foot.²⁹

Further Insights on Antibiotic Therapy

There are many considerations in choosing an antibiotic for the most appropriate situation, including the spectrum of activity, mechanism of action, adverse effects, absorption rate, peak concentrations, clearance routes, and current guidelines for use.

There are common misconceptions about antibiotic drug characteristics, such as the belief that bacteriostatic agents are inferior to bactericidal agents. In fact, bactericidal antibiotics are just as efficacious as bacteriostatic drugs.³⁰ However, many agents that are typically labeled bactericidal typically fail to kill every organism and many labeled bacteriostatic do kill bacteria at higher concentrations.³¹ Most antibacterial agents have both bacteriostatic and bactericidal properties. Another prevalent behavior is routine collection of mycobacterial cultures, which a study recently showed to have no clinical significance in diabetic foot infections.³²

In our diabetic and immunocompromised populations, gram-negative infections occur at an increased rate. However, gram-negative pathogens are difficult to target structurally compared to gram-positive pathogens and becoming increasingly resistant to established therapies. In addition to gram-negative infections compromised patients are often found to have polymicrobial infections.³³ A 16S rRNA analysis has shown that deep ulcers have a more diverse bacterial community as they are colonized by anaerobes, gram-positives, and gram-negative bacteria.³⁴ Diabetic foot ulcers of longer duration have a polymicrobial diversity ranging from an average of 10 to 125 bacterial species.³⁴ Due to increased and diverse microbial load, aggressive debridement is necessary in conjunction with targeted antibiotic therapy. Oftentimes these patients require combination therapies specified by infectious disease providers.²⁸

A closer look at the antibiotic options available is needed moving forward. A strong relationship with infectious disease consultants should be established both in the inpatient and outpatient settings. A foundational knowledge of treatment of SSTI should begin with understanding of Infectious Diseases Society of America guidelines.⁵ Next, familiarity with the local and hospital antibiotic resistance and susceptibility rates is needed. Easily summarized antibiograms can be provided by hospital pharmacists or infectious disease coordinators.

Finally, providers should embrace proper antimicrobial stewardship, along with recognition of the ever-changing landscape of antibiotic management including the availability of new novel and effective therapies.

Dr. Ferryanto is a podiatric medicine and surgery resident at Ascension Health Saint Joseph Hospital in Chicago.

Dr. Owor is a podiatric medicine and surgery resident at Ascension Health Saint Joseph Hospital in Chicago.

Dr. Syed is a podiatric medicine and surgery resident at Heritage Valley Beaver in Beaver, PA.

Dr. Patel practices at Horizon Foot and Ankle Institute in St. Louis.

References

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