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ARTICLE

Acute Bacterial Skin and Skin Structure Infections: A Modernized Approach

AUG 08, 2019 | KERRY CLEVELAND, MD, FACP, FIDSA, FSHEA
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Disclosures and Acknowledgements   

Every day, we are exposed to thousands of microorganisms that inhabit our living spaces and our bodies. In fact, nearly one-third of us have harmless Staphylococcus aureus (staph) on our skin or in our noses.1  However, just a small scratch or insect bite can provide an entryway for staph bacteria to cause a skin infection.2  More and more, health care providers are facing challenges when making prescribing decisions to treat these routine infections.3

I have observed an increasing number of methicillin-resistant Staphylococcus aureus (MRSA) infections in the community. Patients with acute bacterial skin and skin structure infections (ABSSSI) are being seen in hospitals having failed their initial antibiotic course, with worsening symptoms that warrant either admission or an observation unit stay.  

One patient‡ I recently treated contracted a bacterial skin infection after having surgery to place an arteriovenous fistula in her arm for hemodialysis. The patient was initially given intravenous vancomycin. Several weeks after her initial surgery, she presented with fever as well as pain, erythema, and drainage at the surgical site. Surgical exploration and debridement revealed that the infection was only superficial. A culture of the drainage, as well as a nasopharyngeal swab, tested positive for MRSA.  

Treatment Challenges in Acute Bacterial Skin and Skin Structure Infections

Cases like this are playing out at health care centers in the US and around the world. The emergence of hospital- and community-based MRSA4 and other resistant gram-positive pathogens have made ABSSSI a critical public health challenge.5  Skin and soft tissue infections, which include ABSSSI, have been estimated to cause 3.4 million emergency department visits6 and cost roughly $4.5 billion.7 Nearly 80 percent of the infections are caused by staph; roughly half (46 percent) of these are due to MRSA.8 Surgical site infections, often due to MRSA, can necessitate prolonged hospitalization, readmission or costly surgery and could lead to devastating medical complications, disfigurement, disability, or even death.9,10

Many people with ABSSSI who have few or no comorbidities or other serious risk factors can often be treated as outpatients with an appropriate broad-spectrum oral antibiotic.11 Patients with underlying comorbidities including diabetes and vascular disease are considered higher-risk11; they may present with painful, pus-filled abscesses, swelling, or a high temperature and should be closely monitored in the hospital.11
 
Antibiotic Stewardship and Best Practices in Managing ABSSSI

An estimated 750,000 people are hospitalized in the US each year for ABSSSI,12 at a cost that is about 25-40 percent higher than outpatient care.13 Antibiotic stewardship initiatives, such as the World Health Organization’s AWaRe (Access, Watch, and Reserve) program, play a critical role in promoting appropriate antibiotic use to optimize patient outcomes and minimize health care costs without adversely affecting the quality of care.14,15 To align with these goals, health care providers should consider selection of treatment to transition appropriate ABSSSI patients from intravenous (IV) to oral antibiotics. This may help reduce costs by shifting care to the outpatient setting or by facilitating earlier discharge of hospitalized patients.16,17

In my experience, I have found it to be an obstacle that certain widely used IV antibiotics for ABSSSI caused by MRSA don’t have a direct oral equivalent that has polymicrobial coverage to help facilitate outpatient care in appropriate patients.

NUZYRA® (omadacycline): A Modernized Tetracycline to Treat ABSSSI

In line with the mission of antibiotic stewardship, newer antibiotics with both IV and oral options, offer health care providers alternatives for treating appropriate patients.

Approved by the US Food and Drug Administration in October 2018, NUZYRA allows adult patients with ABSSSI and community-acquired bacterial pneumonia (CABP) caused by susceptible gram-positive, gram-negative, and drug-resistant microorganisms to be treated from hospital to home.18

In addition to having both once-daily IV and oral formulations, NUZYRA requires no dosage adjustments in patients with renal or hepatic impairment. NUZYRA represents a modernized tetracycline, which was designed to overcome the most common mechanisms of tetracycline resistance (active efflux pumps and ribosomal protection proteins).18 Unlike older generations of tetracyclines, NUZYRA maintains activity against select tetracycline-resistant pathogens.19  

In the ABSSSI clinical trials, the most common side effects observed in patients taking NUZYRA were nausea, vomiting, and infusion site reactions.18 I recommend NUZYRA as an option for patients who are taking medications that may interact with oral oxazolidinones, or for those who are allergic to beta-lactam antibiotics.§

In the patient case I mentioned earlier, I chose to change her treatment to once-daily oral NUZYRA to potentially avoid drug-drug interactions§, and she was subsequently discharged from the hospital. She experienced some mild nausea upon initiation of NUZYRA, which resolved after two days. After a complete course of therapy and meticulous wound care, she recovered completely. The fistula was salvaged.

Moving Forward Through Antibiotic Stewardship

In my opinion, the looming threat of antibiotic-resistant infections is an opportunity for health care providers to utilize novel approaches to treatment. For the health and well-being of our patients with ABSSSI, we should rethink old habits while also following stewardship practices, such as choosing therapeutic options that have the potential to reduce prolonged hospital stays. In an environment that is increasingly shifting care to the outpatient setting, it is critical to choose the right antibiotic first, for your patients, and to explore novel options that could successfully bridge the gap to home.

INDICATIONS AND USAGE
NUZYRA® is a tetracycline-class antibacterial indicated for the treatment of adult patients with the following infections caused by susceptible microorganisms:

Community-Acquired Bacterial Pneumonia (CABP) caused by the following:
Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae.

Acute Bacterial Skin and Skin Structure Infections (ABSSSI) caused by the following:
Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Staphylococcus lugdunensis, Streptococcus pyogenes, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Enterococcus faecalis, Enterobacter cloacae, and Klebsiella pneumoniae.

USAGE
To reduce the development of drug-resistant bacteria and maintain the effectiveness of NUZYRA and other antibacterial drugs, NUZYRA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS
NUZYRA is contraindicated in patients with known hypersensitivity to omadacycline or tetracycline class antibacterial drugs, or to any of the excipients.

WARNINGS AND PRECAUTIONS
Mortality imbalance was observed in the CABP clinical trial with eight deaths (2%) occurring in patients treated with NUZYRA compared to four deaths (1%) in patients treated with moxifloxacin. The cause of the mortality imbalance has not been established. All deaths, in both treatment arms, occurred in patients > 65 years of age; most patients had multiple comorbidities. The causes of death varied and included worsening and/or complications of infection and underlying conditions. Closely monitor clinical response to therapy in CABP patients, particularly in those at higher risk for mortality.

The use of NUZYRA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and enamel hypoplasia.

The use of NUZYRA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth.

Hypersensitivity reactions have been reported with NUZYRA. Life-threatening hypersensitivity (anaphylactic) reactions have been reported with other tetracycline-class antibacterial drugs. NUZYRA is structurally similar to other tetracycline-class antibacterial drugs and is contraindicated in patients with known hypersensitivity to tetracycline-class antibacterial drugs. Discontinue NUZYRA if an allergic reaction occurs.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs.

NUZYRA is structurally similar to tetracycline-class of antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests), have been reported for other tetracycline-class antibacterial drugs, and may occur with NUZYRA. Discontinue NUZYRA if any of these adverse reactions are suspected.
Prescribing NUZYRA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

ADVERSE REACTIONS
The most common adverse reactions (incidence ≥2%) are nausea, vomiting, infusion site reactions, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hypertension, headache, diarrhea, insomnia, and constipation.

DRUG INTERACTIONS
Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage while taking NUZYRA. Absorption of tetracyclines, including NUZYRA is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron containing preparations.

USE IN SPECIFIC POPULATIONS
Lactation: Breastfeeding is not recommended during treatment with NUZYRA.

To report SUSPECTED ADVERSE REACTIONS, contact Paratek Pharmaceuticals, Inc. at 1-833-727-2835 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please click here for Full Prescribing Information; also available at www.NUZYRA.com.

References:
  1. Otto M. Staphylococcus colonization of the skin and antimicrobial peptides. Expert Rev Dermatol. 2010;5(2):183-195.
  2. Ki V, Rotstein C. Bacterial skin and soft tissue infections in adults: A review of their epidemiology, pathogenesis, diagnosis, treatment and site of care. Can J Infect Dis Med Microbiol. 2008;19(2):173–184.
  3. Pulido-Cejudo A, et al. Ther Adv Infectious Dis 2017; 4(5):143–161
  4. Creech CB, Al-Zubeidi DN, Fritz SA. Prevention of recurrent staphylococcal skin infections. Infect Dis Clin North Am. 2015;29(3):429-464.
  5. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. https://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf.  Accessed on June 6, 2019.
  6. Pallin, Daniel J. et al. Increased US Emergency Department Visits for Skin and Soft Tissue Infections, and Changes in Antibiotic Choices, During the Emergence of Community-Associated Methicillin-Resistant Staphylococcus aureus. Ann Emerg Med. 2008 Mar;51(3):291-8.
  7. Suaya JA, Mera RM, Cassidy A, O'Hara P, Amrine-Madsen H, Burstin S, et al. Incidence and cost of hospitalizations associated with Staphylococcus aureus skin and soft tissue infections in the United States from 2001 through 2009. BMC Infect Dis. 2014; 14(1):296.
  8. Ray GT, Suaya JA, Baxter R. Incidence, microbiology, and patient characteristics of skin and soft-tissue infections in a U.S. population: a retrospective population-based study. BMC Infect Dis. 2013;13:252.
  9. Lee BY, Singh A, David MZ, et al. The economic burden of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). Clin Microbiol Infect. 2013;19(6):528–536.
  10. Muralidhar, B, Anwar SM, et al. Prevalence of MRSA in Emergency and Elective Patients Admitted to a Vascular Surgical Unit: Implications for Antibiotic Prophylaxis. European Journal of Vascular and Endovascular Surgery, 2006;32(4):402-407.
  11. Ramakrishnan K, Salinas RC, Agudelo Higuita NI. Skin and soft tissue infections. Am Fam Physician. 2015 Sep 15;92(6):474-483.
  12. Kaye KS, Patel DA, Stephens JM, Khachatryan A, Patel A, Johnson K (2015) Rising United States Hospital Admissions for Acute Bacterial Skin and Skin Structure Infections: Recent Trends and Economic Impact. PLoS ONE 10(11): e0143276.
  13. Ross, MA, Hockenberry, JM, et al. Protocol-Driven Emergency Department Observation Units Offer Savings, Shorter Stays, And Reduced Admissions. Health Affairs. 2013 Dec;32(12):2149-56
  14. Trivedi KK, Pollack LA. The role of public health in antimicrobial stewardship in healthcare. Clin Infect Dis. 2014;59:101-103.
  15. World Health Organization. AWaRe Policy Brief. Available at https://adoptaware.org/resources/AWaRe_Policy_Brief.pdf; Accessed on July 16, 2019.
  16. Cyriac JM, James E. Switch over from intravenous to oral therapy: a concise overview. J Pharmacol Pharmacother. 2014 Apr-Jun;5(2):83-87.
  17. Barlam et al. Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016 May 15;62(10):e51-77.
  18. NUZYRA® [Prescribing Information]. Boston, MA: Paratek Pharmaceuticals, Inc.; 2019
  19. Draper MP, Weir S, Macone A, et al. Mechanism of action of the novel aminomethylcycline antibiotic omadacycline. Antimicrob Agents Chemother. 2014;58(3):1279–1283.

Disclosures and Acknowledgements 
This article is sponsored by Paratek Pharmaceuticals, Inc. 
Dr. Cleveland serves as an advisor for Paratek and has participated in the conceptualization, drafting, and revision of this article. He has been compensated for his time. 
Third-party editorial assistance has been provided in compliance with ethical industry standards. 
Real patient de-identified based on HIPAA requirements.  
 
§NUZYRA is not expected to interact with drugs metabolized by cytochrome P450 enzymes. Patients on anticoagulant therapy may require downward adjustment of their anticoagulant dosage while taking NUZYRA. Absorption of oral tetracyclines, such as NUZYRA, is impaired by antacids containing aluminum, calcium or magnesium bismuth subsalicylate and iron containing preparations.
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