Pharmacology Consult

Opioid epidemic poses treatment conundrums for community-acquired MRSA infections

Staphylococcus aureus continues to be a pathogen associated with significant morbidity and mortality. This pathogen has long coexisted with humans, and its unique mechanisms of resistance have allowed it to evolve. Arguably, S. aureus has been one of the most persistent pathogens in health care settings and the community because it has the propensity to cause a wide array of diseases. These most commonly include skin and soft tissue infections, complicated bloodstream infections and endocarditis, making treatment strategies difficult. Continued focus and efforts are required to control and treat this significant player in human disease. Although health care-associated disease was a large focus in the late 1990s and early 2000s, community-acquired MRSA (CA-MRSA) has been slowly emerging as more problematic.

The opioid epidemic is one factor contributing to the increase in community-acquired S. aureus infections, including MRSA. Nonsterile injection practices likely contribute to the increase in this type of infection. In the United States, we continue to see increasing rates of opioid overdoses. The CDC noted that in the past 18 years, almost 400,000 people have died from overdose of opioids. By 2017, deaths involving opioid overdoses were six times higher than in 1999. IV drug use (IVDU) is a risk factor for CA-MRSA skin and soft tissue infections (SSTIs); however, it is becoming increasingly clear that IVDU is increasing the risk for more significant, life-threatening infections presenting from the community. A study published by Jackson and colleagues showed that invasive MRSA cases of injection drug users have increased from 4.1% in 2011 to 9.2% in 2016, and these patients are 16.3 times more likely to develop invasive MRSA over other infections.

Treatment conundrums

This patient population offers some unique challenges to designing a pharmacotherapeutic plan for the management of their infection. What is the primary site of infection? Can more invasive MRSA infection be ruled out? What is the best drug and route of administration for this patient? Is it safe to place a central line for IV antibiotics? Will they adhere to treatment? And do they have insurance or other means to cover medication costs? The Infectious Diseases Society of America’s 2011 guidelines for treatment of MRSA infections in adults and children are the most up-to-date guidelines available, but they do not address the newer antibiotic agents that have been approved by the FDA. Additionally, more recently published data appear to support oral step-down therapy for invasive S. aureus infections in this patient population.

Kimberly D. Boeser

Oral antibiotic treatment regimens for CA-MRSA SSTIs are relatively straightforward, and several options that are safe, effective and generally well-tolerated are available. Trimethoprim/sulfamethoxazole and doxycycline are more cost-effective than other oral agents such as linezolid or tedizolid. If more complicated disease is present, such as bacteremia, IV therapy is preferred. Vancomycin and daptomycin continue to be the mainstay, first-line treatment for MRSA bacteremia. However, these require central lines for administration, some level of therapeutic drug monitoring (TDM) for vancomycin, and follow-up laboratory monitoring. Advancements in home infusion practices have allowed outpatient parenteral antimicrobial therapy to become a common practice. However, in persons who inject drugs, discharging a patient with a central line carries a higher level of risk, and follow-up and compliance are often problematic. The newer agents in the lipoglycopeptide class may offer a solution.

The lipoglycopeptides

The lipoglycopeptides Vibativ (telavancin, Cumberland Pharmaceuticals), Dalvance (dalbavancin, Allergan) and Orbactiv (oritavancin, Melinta Therapeutics) have struggled to find their niche in clinical practice. These agents have some similarities to vancomycin, but there are some profound differences. Both vancomycin and the lipoglycopeptides have FDA-labeled indications for SSTIs, cover a wide spectrum of gram-positive pathogens like MRSA and have concentration-dependent bactericidal activity. However, dalbavancin and oritavancin have appealing drug properties, including one-time dosing, no TDM requirements and no need for dose adjustments based on renal impairments. These agents allow for more rapid discharge and require minimal follow-up from the drug administration perspective.

Treatment with oral antibiotics for more invasive disease

For patients who present with invasive MRSA infection such as bacteremia or endocarditis, IV therapy for an extended period (up to 6 weeks) has been the primary recommendation. Historically, transitioning to an oral therapy regimen for these indications has not been well supported. In the injection drug user population, where a central line has a propensity for abuse and long-term admission for IV antibiotics is not economically feasible, supporting evidence for the transition to oral therapy would be welcomed in clinical practice.

A randomized study recently published in The New England Journal of Medicine by Iversen and colleagues showed that changing to oral antibiotics was noninferior to continued IV antibiotic therapy in patients with infective endocarditis. Unfortunately, the study included only a handful of patients with IV drug use and no patients with MRSA infections.

Conclusions

The opioid epidemic has thrust CA-MRSA infections into the spotlight. The approach to designing a safe and effective therapeutic plan is really tailored to each patient. This includes an assessment of their current IVDU status, their risk for abuse, whether more invasive disease is present, their compliance to medication and the ability to ensure treatment follow-up. The one-time dose of lipoglycopeptides is an appealing alternative to the standard of care but lipoglycopeptides are limited to SSTIs; they have not been evaluated for the treatment for bacteremia or endocarditis. Additionally, these newer agents are still extremely cost prohibitive. Both dalbavancin and oritavancin have reported relatively good safety profiles, but with their extended half-life, extensive protein binding and limited removal from dialysis, how do we manage a patient who experiences a significant adverse effect or a life-threatening allergic reaction? Additionally, transition to oral antibiotics rather than placing a central line in this population is often considered, but this practice has yet to be supported by evidence. The recent Iverson study had a limited IVDU population and no MRSA cases, and extensive follow-up was part of the strategy.

New, targeted research in this population is desperately needed.

Find more information about the unique properties of oritavancin and dalbavancin, published in the October 2015 Pharmacology Consult.

Disclosure: Boeser reports no relevant financial disclosures.

Staphylococcus aureus continues to be a pathogen associated with significant morbidity and mortality. This pathogen has long coexisted with humans, and its unique mechanisms of resistance have allowed it to evolve. Arguably, S. aureus has been one of the most persistent pathogens in health care settings and the community because it has the propensity to cause a wide array of diseases. These most commonly include skin and soft tissue infections, complicated bloodstream infections and endocarditis, making treatment strategies difficult. Continued focus and efforts are required to control and treat this significant player in human disease. Although health care-associated disease was a large focus in the late 1990s and early 2000s, community-acquired MRSA (CA-MRSA) has been slowly emerging as more problematic.

The opioid epidemic is one factor contributing to the increase in community-acquired S. aureus infections, including MRSA. Nonsterile injection practices likely contribute to the increase in this type of infection. In the United States, we continue to see increasing rates of opioid overdoses. The CDC noted that in the past 18 years, almost 400,000 people have died from overdose of opioids. By 2017, deaths involving opioid overdoses were six times higher than in 1999. IV drug use (IVDU) is a risk factor for CA-MRSA skin and soft tissue infections (SSTIs); however, it is becoming increasingly clear that IVDU is increasing the risk for more significant, life-threatening infections presenting from the community. A study published by Jackson and colleagues showed that invasive MRSA cases of injection drug users have increased from 4.1% in 2011 to 9.2% in 2016, and these patients are 16.3 times more likely to develop invasive MRSA over other infections.

Treatment conundrums

This patient population offers some unique challenges to designing a pharmacotherapeutic plan for the management of their infection. What is the primary site of infection? Can more invasive MRSA infection be ruled out? What is the best drug and route of administration for this patient? Is it safe to place a central line for IV antibiotics? Will they adhere to treatment? And do they have insurance or other means to cover medication costs? The Infectious Diseases Society of America’s 2011 guidelines for treatment of MRSA infections in adults and children are the most up-to-date guidelines available, but they do not address the newer antibiotic agents that have been approved by the FDA. Additionally, more recently published data appear to support oral step-down therapy for invasive S. aureus infections in this patient population.

Kimberly D. Boeser

Oral antibiotic treatment regimens for CA-MRSA SSTIs are relatively straightforward, and several options that are safe, effective and generally well-tolerated are available. Trimethoprim/sulfamethoxazole and doxycycline are more cost-effective than other oral agents such as linezolid or tedizolid. If more complicated disease is present, such as bacteremia, IV therapy is preferred. Vancomycin and daptomycin continue to be the mainstay, first-line treatment for MRSA bacteremia. However, these require central lines for administration, some level of therapeutic drug monitoring (TDM) for vancomycin, and follow-up laboratory monitoring. Advancements in home infusion practices have allowed outpatient parenteral antimicrobial therapy to become a common practice. However, in persons who inject drugs, discharging a patient with a central line carries a higher level of risk, and follow-up and compliance are often problematic. The newer agents in the lipoglycopeptide class may offer a solution.

The lipoglycopeptides

The lipoglycopeptides Vibativ (telavancin, Cumberland Pharmaceuticals), Dalvance (dalbavancin, Allergan) and Orbactiv (oritavancin, Melinta Therapeutics) have struggled to find their niche in clinical practice. These agents have some similarities to vancomycin, but there are some profound differences. Both vancomycin and the lipoglycopeptides have FDA-labeled indications for SSTIs, cover a wide spectrum of gram-positive pathogens like MRSA and have concentration-dependent bactericidal activity. However, dalbavancin and oritavancin have appealing drug properties, including one-time dosing, no TDM requirements and no need for dose adjustments based on renal impairments. These agents allow for more rapid discharge and require minimal follow-up from the drug administration perspective.

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Treatment with oral antibiotics for more invasive disease

For patients who present with invasive MRSA infection such as bacteremia or endocarditis, IV therapy for an extended period (up to 6 weeks) has been the primary recommendation. Historically, transitioning to an oral therapy regimen for these indications has not been well supported. In the injection drug user population, where a central line has a propensity for abuse and long-term admission for IV antibiotics is not economically feasible, supporting evidence for the transition to oral therapy would be welcomed in clinical practice.

A randomized study recently published in The New England Journal of Medicine by Iversen and colleagues showed that changing to oral antibiotics was noninferior to continued IV antibiotic therapy in patients with infective endocarditis. Unfortunately, the study included only a handful of patients with IV drug use and no patients with MRSA infections.

Conclusions

The opioid epidemic has thrust CA-MRSA infections into the spotlight. The approach to designing a safe and effective therapeutic plan is really tailored to each patient. This includes an assessment of their current IVDU status, their risk for abuse, whether more invasive disease is present, their compliance to medication and the ability to ensure treatment follow-up. The one-time dose of lipoglycopeptides is an appealing alternative to the standard of care but lipoglycopeptides are limited to SSTIs; they have not been evaluated for the treatment for bacteremia or endocarditis. Additionally, these newer agents are still extremely cost prohibitive. Both dalbavancin and oritavancin have reported relatively good safety profiles, but with their extended half-life, extensive protein binding and limited removal from dialysis, how do we manage a patient who experiences a significant adverse effect or a life-threatening allergic reaction? Additionally, transition to oral antibiotics rather than placing a central line in this population is often considered, but this practice has yet to be supported by evidence. The recent Iverson study had a limited IVDU population and no MRSA cases, and extensive follow-up was part of the strategy.

New, targeted research in this population is desperately needed.

Find more information about the unique properties of oritavancin and dalbavancin, published in the October 2015 Pharmacology Consult.

Disclosure: Boeser reports no relevant financial disclosures.

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