Latest Advancements in Antimicrobial Therapy

Each new option offers advantages in infection management, but also comes with barriers to therapy.

This article was collaboratively written with Zachary Riley, PharmD Candidate 2017 at the Harrison School of Pharmacy at Auburn University.

For many years, antimicrobials have proven instrumental in saving lives. Despite the success of these agents, resistant bacteria continue to infect 2 million patients annually in the United States alone and are responsible for 23,000 deaths per year.

Now, antimicrobial advancements are providing new options for infection management, including previously resistant strains. These new agents can help decrease the spread of resistant microbes by reducing the amount of exposure to ineffective antimicrobials, which can potentiate resistance while exposing patients to unnecessary untoward effects and result in increased health care utilization and costs.1-3

Many of these advancements are direct results of the GAIN Act, which incentivizes companies to discover and develop antibiotics. Each new option offers advantages in infection management, but also comes with barriers to therapy.

IV Products

Dalbavancin (Dalvance)

The FDA approved dalbavancin on May 23, 2014, for treating acute bacterial skin and skin structure infections (SSTIs) caused by methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Streptococcus pyogenes.

Dalbavancin is unique in that it can be given once-weekly because of its long half-life of 170-210 hours. For SSTIs, a single dose of 1500 mg or a 2-dose regimen of 1000 mg followed by a 500 mg dose a week later is recommended. This provides benefit over vancomycin’s daily administration requirement.

If a patient is hospitalized, 1 dose can be given before discharge. If the single dose regimen is used, the patient doesn’t have to be discharged home with an indwelling line or home health services specifically for medication administration. This can benefit patients who have limited insurance coverage, are nonadherent, or are unable to use home vancomycin therapy for other reasons.

Dalbavancin is infused over 30 minutes, presenting the patient with a possible inconvenience of an outpatient infusion clinic visit if the medication can’t be administered by a local home health nurse. Additionally, dalbavancin may cause gastrointestinal effects like nausea, headache, and diarrhea, along with increased liver enzymes. However, the agent’s risk of skin effects like red man syndrome, which is associated with vancomycin use, is minimized if the infusion is administered over at least 30 minutes.

Clinical trials indicated dalbavancin treats acute SSTIs with similar efficacy as vancomycin. Against β-hemolytic streptococci, dalbavancin had a lower minimum inhibitory concentration (MIC) to kill 90% (MIC90) of the bacteria at 0.047, versus vancomycin’s MIC90 of 0.75.

MRSA is more susceptible to dalbavancin (100%) than vancomycin (99.8%) and traditional oral options like clindamycin (55.2%), tetracycline (91.8%), and linezolid (99.7%).4 Although the latter options may be less expensive, they require multiple daily dosing that opens the door for nonadherence.

Overall, dalbavancin offers an easier way to treat SSTIs in patients with known Gram-positive infections.

Oritavancin (Orbactiv)

Oritavancin was approved on August 6, 2014, for the treatment of acute bacterial SSTIs caused by MSSA, MRSA, and some Streptococcus species. It’s infused in a single dose of 1200 mg over 3 hours.

Unlike dalbavancin, oritavancin is approved to treat Enterococcus faecalis—an increasingly common cause of SSTI, with some strains known to be resistant to vancomycin. Oritavancin has similar efficacy as vancomycin for SSTIs, including those caused by S. aureus (81.8% vs 81.9%), wound with MRSA (22.1% vs 20.0%), cellulitis (51.2% vs 48.6%), cellulitis with MRSA (19.2% vs 23%) , abscess (29.5% vs 29.5%), and abscess with MRSA (58.7% vs 57%). Unlike vancomycin and dalbavancin, it demonstrates activity against VanA and VanB-mediated vancomycin-resistant enterococci (VRE) with a MIC90 of 1 for VanA and 0.06 for VanB.

Increased liver enzymes associated with dalbavancin and red man syndrome associated with vancomycin aren’t concerns with oritavancin, but common side effects include headache, diarrhea, nausea, vomiting, and skin and soft tissue abscesses on arms and legs. Plus, oritavancin should be avoided in those suspected of having osteomyelitis.

Oritavancin inhibits CYP2C9 and may increase warfarin’s serum concentration by as much as 30%. INR should be monitored 24 hours after oritavancin administration at a minimum, but close monitoring for about 10 days wouldn’t be unreasonable given oritavancin’s 245-hour half-life and relative unknown impact on INR beyond the first 24 hours.

Interestingly, oritavancin doesn’t directly affect coagulation, but it falsely prolongs activated partial thomboplastin time (aPTT) for up to 120 hours after administration by binding to the phospholipid reagents. Other drugs requiring aPTT monitoring (eg, heparin) should be avoided within this 5-day period.

Ceftolozane/tazobactam (Zerbaxa)

This fifth-generation cephalosporin was approved on December 19, 2014, for complicated intra-abdominal infections (cIAIs) (with metronidazole) and complicated UTIs in adults. Ceftolozane isn’t commercially available without the beta-lactamase inhibitor tazobactam, which provides coverage against some drug-resistant bacteria.

Dosing for cIAIs is 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) IV every 8 hours with metronidazole 500 mg IV every 8 hours for 4 to 14 days. Dosing is the same for UTIs with a recommended 7-day duration, but without the metronidazole.

Ceftolozane/tazobactam has similar efficacy in cIAI treatment as meropenem with a clinical cure rate of 91% when used with metronidazole, versus 94% with meropenem.5 In UTI treatment, the ceftolozane/tazobactam covered a patient group with majority Enterobacteriaceae infections and MIC < 2mg/L. Against levofloxacin-resistant bacteria, ceftolozane/tazobactam had an expected higher cure rate than levofloxacin in a microbiological-modified population (60% vs. 39.3%) and microbiologically-evaluable population (64% versus 43.4%).

Despite this advantage, overall cure rates appear suboptimal and selection of ceftolozane/tazobactam as empiric therapy in areas with high fluoroquinolone resistance should be weighed against the severity of the infection. Ceftolozane/tazobactam wasn’t as effective in patients with kidney impairment (CrCl 30-50 mL/min), but there are concerns that the population studied was underdosed; therefore, its true efficacy in patients with baseline CrCl <50mL/min remains somewhat unknown.6 Nevertheless, until more data are available, ceftolozane/tazobactam shouldn’t be initiated in these patients.

At first glance, it appears caftolozane/tazobactam would add little advantage to antibiotic treatment other than in a stewardship role of reducing exposure to broader-spectrum agents. However, it does provide an alternative to fluoroquinolones when QT prolongation is a concern. Observed side effects in clinical trials were similar to other cephalosporins.

Ceftazidime/avibactam (Avycaz)

The FDA approved ceftazidime/avibactam on February 25, 2015. It’s a combination of an older antibiotic (ceftazidime) with a new beta-lactamase inhibitor (avibactam) that allows ceftazidime to fight infections without the hindrance of beta-lactamases.

Avibactam has unique chemical properties providing a broad spectrum of activity that includes some strains of multidrug-resistant, Gram-negative organisms like Pseudomonas aeruginosa. It’s approved to treat cIAI (with metronidazole), complicated UTIs, and pyelonephritis.

Ceftazidime/avibactam 2.5 g/0.5 g IV is given every 8 hours.

Ceftazidime/avibactam with metronidazole has a 93.4% favorable clinical outcome for cIAI comparable to meropenam at 92.1%.7 It’s just as effective as imipenan-cilastin for UTIs and pyelonephritis with 71.4% response without ceftazidime-resistant uropathogens and 85.7% with ceftazidime-resistant pathogens versus 70.4% overall for imipenam-clilastin.8 This would help decrease carbapenem exposure, which in turn could help slow the development of resistance to one of the broadest-spectrum antibiotic classes. This is an important consideration given the growing number of carbapenem-resistant organisms. Likewise, the avibactam component could potentially treat carbapenem-resistant organisms.

Vomiting, nausea, constipation, and anxiety are common side effects associated with ceftazidime/avibactam. In cases of poor kidney function, some patients experienced seizures and other neurotoxic effects. Other antibiotics may be best for patients with decreased renal function and/or history of seizures.

Obiltoxaximab (Anthim)

Obiltoxaximab was approved on March 18, 2016, for the treatment and prophylaxis of inhalational anthrax. Bacillus anthracis infects patients via spores that enter the respiratory tract which can result in a fatal infection.

Obiltoxaximam can cause anaphylaxis and patients should be pretreated with a dose of diphenhydramine. For adults <40 kg, a single dose at 24 mg/kg IV is given, while those >40 kg should receive a single dose of 16 mg/kg IV. All doses should be infused over a minimum of 90 minutes, and patients should be monitored for anaphylaxis closely during and after administration.

Human studies for obiltoxaximab haven’t been conducted, but animals given obiltoxaximab lived longer than those given placebo. Safety trials indicated the risk of experiencing anaphylaxis outweighs the benefits of continued anthrax infection. Other adverse events were headache, itching, upper respiratory tract infections, cough, nasal congestion, hives, and bruising, swelling, and pain at the infusion site.

Obiltoxaximab may be an alternative for fluoroquinolones and doxycycline when these agents aren’t available or inappropriate.

Oral Products

Isavuconazonium sulfate (Cresemba)

Isavuconazonium sulfate is an antifungal approved with orphan drug designation on March 6, 2015, for the treatment of invasive aspergillosis and invasive mucormycosis. These rare infections occur most often in immunosuppressed patients.

Isavuconazonium is available in both oral and IV formulations. It’s dosed at 372 mg every 8 hours for 6 doses, followed by 372 mg once every 24 hours thereafter. In clinical studies, it was found similarly effective to voriconazole.

Isavuconazonium may cause GI adverse effects (nausea/vomiting/diarrhea/constipation) and headache. More serious adverse effects include abnormal liver tests, hypokalemia, dyspnea, and peripheral edema. However, it may be an alternative treatment for patients with history of delusions or who may be on drugs that cause visual disturbances. Using isavuconazonium avoids the hallucinations and visual disturbances that may be experienced with voriconazole.

In phase 3 studies, isavuconazonium sulfate was found noninferior to voriconazole as a broad-spectrum antifungal. Trials indicated 42 days after one dose of each drug, isavuconazonium sulfate caused an all-cause mortality rate of 19%, compared with voriconazole’s 20%.

Tedizolid phosphate (Sivextro)

Tedizolid phosphate was approved on June 20, 2014, for the treatment of SSTIs and associated susceptible bacteria, MRSA, MSSA, various Streptococcus species, and Enterococcus species. It can be given orally or through IV at 600 mg daily for 6 days—an advantage over linezolid, which requires twice-daily dosing for 10 to 14 days. If a dose is missed, it can be taken as long as the next scheduled dose isn’t within 8 hours.

Adverse effects like nausea, headache, diarrhea, vomiting, and dizziness are common with tedizolid. Although tedizolid inhibits monoamine oxidase in vitro, it’s probability for inducing serotonin syndrome at therapeutic doses is low, which provides another advantage over linezolid.

Tedizolid was proven effective as linezolid in the treatment of Staphylococcus aureus and MRSA, with a difference of 0.1%. It may also be effective against strains of VRE and linezolid-resistant bacteria, which is increasingly isolated throughout the United States.

Topical Products

Efinaconazole (Jublia) 10% topical gel

Efinaconazole is an antifungal approved on June 6, 2014, for the treatment of fungal toenail infections. It’s painted on each affected toenail, including the toenail end, once-daily for 48 weeks.9 Compared with oral itraconazole, efinaconazole outcomes were similar in efficacy, and it has cure rates that are 3 to 4 times better than ciclopirox, another nail polish indicated for toenail fungal infections.10 Although seen in very few patients, adverse effects included ingrown toenail, itchy skin, inflammation, rash, and pain (1%-2% of patients).9-11

Trial results suggest efinaconazole has efficacy for richophyton rubrum or trichopyton mentagrophytes infections. At 52 weeks’ treatment, 39.2% of patients were cured or almost cured with the drug, whereas only 10.2% of patients were cured or almost cured without it.10

Tavaborole (Kerydin)12

Tavaborole is the first oxaborole antifungal agent approved June 6, 2014, for the treatment of toenail infections caused by trichophyton rubrum or trichophyton mentagrophytes fungi. By aminoacyl-transfer ribonucleic acid (tRNA) synthetase (AARS) inhibition, tavaborole stops fungal protein synthesis. Like efinaconazole, it’s applied topically daily to the infected toenail for 48 weeks.

In clinical trials, patients using tavaborole experienced cure rates of 31.1% and 35.9% versus 7.2% and 12.2% in patients treated with placebo. Tavaborole seems a good alternative when other antifungal therapy has failed.

When using tavaborole, patients may see application site exfoliation, ingrown toenail, application site erythema, and application site dermatitis, but these effects were only seen in 1% of patients.

1.2% clindamycin/3.75% benzoyl peroxide (Onexton)

Topical clindamycin/benzoyl peroxide was approved November 25, 2014, for the treatment of acne vulgaris. It’s topically applied once-daily in adults 12 years and older. It’s the only fixed clindamycin/benzoyl peroxide combination, giving double treatment against the infection, whereas other treatments only offer single-drug treatment.

Adverse events were only seen in 1% of patients in clinical trials. Burning sensation, dermatitis contact, pruritus, and rash were observed, but it should be noted no patients discontinued treatment due to adverse events.

Ear Drops

Ciprofloxacin/fluocinolone (Otovel)

This fluoroquinolone/corticosteroid combination eardrop was approved April 29, 2016, for the treatment of acute otitis media associated with S. aureus, Streptococcus pneumoniae, Haemophilus influenza, Moraxella catarrhalis, and P. aeruginosa. It’s given to adults and children at least 6 months old twice-daily for 7 days. Presently, its availability in the market isn’t substantial.13

Adverse events include hypersensitivity, otorrhea, excessive granulation tissue, ear infection, ear pruritus, tympanic membrane disorder, auricular swelling and balance disorder (>1%).

Finafloxacin (Xtoro)

The FDA approved the eardrop finafloxacin for acute otitis externa, or swimmer’s ear, on December 17, 2014. Adults should take 4 drops twice daily for 7 days.

Finafloxacin covers P. aeruginosa and S. aureus associated with swimmer’s ear in 70% of patients in clinical trials. It also showed coverage against B. fragilis and anaerobic bacteria (comparable to moxifloxacin).14 Patients experienced nausea and pruritus as common adverse effects.

Anthelmintics

Mebendazole (Emverm)

Mebendazole was approved January 15, 2016, for the wide-range treatment of Ancylostoma duodenale or Necator americanus (hookworm), Ascariasis (roundworm), Enterobiasis (pinworm), Strongyloidiasis (roundworm), Trichuriasis (whipworm), and Taeniasis (tapeworm).15 It’s generally dosed at 100 mg orally twice-daily for 3 days or 100 mg orally in a single dose. If the initial treatment fails, the treatment can be repeated in 3 weeks of the first treatment.

It’s unique because it treats pinworm at a rate of 95% with the initial dose compared with other agents. It’s noteworthy that Hydatid disease wasn’t adequately treated despite using high doses. Neutropenia and agranulocytos were seen with higher-than-recommended dosing for long-term treatment; therefore, it’s important to administer the exact recommended dose, especially in patients with a history or high risk for neutropenia.15

Vaccines

Bexsero

This vaccine prevents Neisseria meningitidis serogroup B invasive meningococcal disease. The FDA approved its use in 10- to 25-year-old patients on January 23, 2015. Two doses are administered separated by 1 month.

Studies concerning Bexsero indicated 62% to 88% of vaccinated patients had antibodies for 3 Neisseria meningitidis serogroup B strains compared with a prevaccination rate of 0% to 23% having antibodies.

Trumenba

Trumenba also prevents N. meningitidis serogroup B invasive meningococcal disease, but it’s different from Bexsero because it can be given in 2- or 3-dose intervals. On October 29, 2014, the FDA the first vaccine approved for its use.

Studies show 82% of patients postvaccine have antibodies for 4 strains N. meningitidis serogroup of compared to <1% at prevaccination.

Neither vaccine should be mixed with other vaccines. Patients should be counseled that they may experience injection site irritation, loss of strength and energy, headache, muscle pain, joint pain, chills, diarrhea, or nausea. Their prescriber must be notified if they experience shortness of breath, severe dizziness, or fainting.

In the Pipeline

Teixobactin

Although still in preclinical studies, teixobactin possibly represents a new era in the fight against microbial infections as the first of a new class, peptidoglycan synthesis inhibitors. Specifically, it binds to a region known as the undecaprenyl-PP-sugar region of lipid II and lipid III. This region isn’t modified by bacterial resistance mechanisms. Teixobactin is potent for many Gram-positive bacteria, including MRSA and VRE.16

Teixobactin was innovatively discovered using an iChip device that searches for microorganisms producing natural antibiotics in the soil to S. aureus. The iChip allows for the discovery of unknown chemicals that could dawn the discovery of more antibiotics and other drugs classes in the future.16,17

Conclusion

Combating antimicrobial resistance is crucial to disease treatment and prevention. Older and proven drugs should still be used first-line whenever possible, reserving the newer agents for resistant infections. Although there’s currently no antibiotic on the market without documented resistance, we can try to preserve the susceptibilities of these new agents for as long as possible.

Collectively, this group of new approvals represents new hope that the possible postantibiotic era won’t be an era of medicinal inadequacy, but a time of ground-breaking discovery in the fight against microbial infections.

References

1. CDC. Antibiotic/antimicrobial resistance. cdc.gov/drugresistance. Published April 19, 2016.

2. Sainato M. The end of the antibiotic era: what you need to know about bacterial resistance. New York Observer. observer.com/2015/11/the-end-of-the-antibiotic-era-what-you-need-to-know-about-bacterial-resistance. Published November 24, 2011.

3. FDA. Combating antimicrobial resistance. fda.gov/ForConsumers/ConsumerUpdates/ucm092810.htm. Published February 19, 2016.

4. Biedenbach DJ, et al. Activity of dalbavancin tested against Staphylococcus spp. and beta-hemolytic Streptococcus spp. isolated from 52 geographically diverse medical centers in the United States. J Clin Microbiol. 2007;45(3):998-1004.

5. Skalweit MJ, et al. Profile of ceftolozane/tazobactam and its potential in the treatment of complicated intra-abdominal infections. Drug Des Devel Ther. 2015; 2015(9): 2919-2925.

6. Huntington JA, et al. Efficacy of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (cUTIs) caused by levofloxacin-resistant pathogens: results from the ASPECT-cUTI trial. J Antimicrob Chemother. 2016.

7. Lucasti C, et al. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother. 2013;68(5):1183-1192.

8. Vazquez JA, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012;28(12):1921-1931.

9. FDA. More Information for Jublia (efinaconazole). fda.gov/Drugs/InformationOnDrugs/ucm423581.htm. Updated March 4, 2015.

10. Hoffman K. A closer look at a new topical option for onychomycosis. Podiatry Today. podiatrytoday.com/blogged/closer-look-new-topical-option-onychomycosis. Updated October 1, 2014.

11. FDA. Drug Trials Snapshot Jublia (efinaconazole). fda.gov/Drugs/InformationOnDrugs/ucm422419.htm. Updated March 4, 2015.

12. FDA approves Anacor Pharmaceuticals' KERYDIN (tavaborole) topical solution, 5% for the treatment of onychomycosis of the toenails. investor.anacor.com/releasedetail.cfm?releaseid=858211. Published July 8, 2014.

13. Otovel patient package insert. accessdata.fda.gov/drugsatfda_docs/label/2016/208251orig1s000lbl.pdf. Published April 2014.

14. Genzel GH, et al. Activity of the investigational fluoroquinolone finafloxacin and seven other antimicrobial agents against 114 obligately anaerobic bacteria. Int J Antimicrob Agents. 2014;44(5):420-423.

15. Impax receives approval of EMVERM (mebendazole) chewable tablets, 100 mg. prnewswire.com/news-releases/impax-receives-approval-of-emverm-mebendazole-chewable-tablets-100-mg-300205033.html. Published January 15, 2015.

16. Piddock L. Teixobactin, the first of a new class of antibiotics discovered by iChip technology? J Antimicrob Chemother. 2015;70(10): 2679-2680.

17. Borel B. ICHIP: THE FUTURE OF ANTIBIOTIC DISCOVERY. popsci.com/ichip-new-way-find-antibiotics-and-other-key-drugs. Published January 20, 2015.