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#PharmToExamTable: Treatment of Necrotizing Pneumonia

A #PharmToExamTable question about MRSA treatment, answered by Traver Pettijohn, PharmD, a 2021 Graduate of UNMC College of Pharmacy who is now a pharmacist at Community Pharmacy.

(Reviewed by Andrew Watkins, PharmD)

Pneumonia, S. aureus, and PVL

Pneumonia is an infection of the lungs caused by the infiltration of microorganisms, such as bacteria, viruses, and fungi, into the lungs of hosts. Many patients diagnosed with bacterial pneumonia are able to be treated in the outpatient setting with oral antibiotics; however, more serious cases may require hospitalization and more aggressive treatment. Staphylococcus aureus is a gram positive, pyogenic bacteria that is associated with superficial skin and soft tissue infections as well as deeper infections including septic arthritis, osteomyelitis, endocarditis, and pneumonia. Community acquired methicillin-resistant S. aureus (CA-MRSA) is of particular concern as it is resistant to beta-lactam antibiotics, which are first-line empiric therapy for many community acquired infections. CA-MRSA has been associated with a form of necrotizing pneumonia (NP) characterized by leukopenia, hemoptysis, and extensive destruction of lung tissue.

Panton-Valentine Leukocidin (PVL) is an exotoxin that is produced by many strains of S. aureus and attacks host immune cells. The majority of CA-MRSA strains in the US produce PVL, which increases the risk of developing necrotizing pneumonia.1 There is controversy surrounding the role PVL plays in CA-MRSA infections in general, but the most compelling data has shown the association of PVL with post-viral NP.2,3 Several studies evaluating PVL as a virulence factor for NP in mice have largely been inconclusive3-8. One study using a rabbit model has demonstrated that PVL plays a critical role in NP infection9. The authors of this study state PVL production is believed to result in the activation of polymorphonuclear (PMN) leukocytes and macrophages, along with accompanying inflammatory cytokines. Once these immune cells are recruited to the site of infection, PVL lyses PMNs, resulting in the release of granules and proteolytic enzymes into the lung tissue which leads to tissue damage.

There have been limited trials assessing the use of antimicrobials for the purpose of toxin suppression in PVL positive CAP, and their place in therapy of NP is thought to be analogous to their role in the treatment of streptococcal and staphylococcal toxic shock syndrome. All studies to date evaluating toxin suppression in PVL producing CA-MRSA strains have been in vitro studies with clindamycin and linezolid being the two most studied and most successful antibiotics for toxin suppression. Current IDSA/ATS Community Acquired Pneumonia (CAP) guidelines do not address the use of antimicrobials for toxin suppression in NP caused by CA-MRSA.10 IDSA guidelines for treatment of MRSA infections do not recommend the routine use of clindamycin or linezolid in treating CA-MRSA except in severe cases of NP as there is limited evidence to support their use.11 The evidence supporting the anti-toxin effects of clindamycin and linezolid in CA-MRSA infections is summarized below.

Clindamycin, Linezolid, and Toxin Suppression

Clindamycin is a lincosamide antibiotic which works by binding the 50s ribosomal subunit of bacteria thus disrupting protein synthesis and creating a bacteriostatic effect. S. aureus bacteria can develop resistance to clindamycin by modification of the 23s ribosome target site that is either inducible or constitutive, with the latter preventing toxin suppression completely in vitro.13,14 Three in vitro studies performed using direct PVL toxin quantification showed that clindamycin inhibited the production of PVL toxin at sub inhibitory concentrations (concentrations below the MIC) as low as 1/8 MIC.12,14,15 Two in vitro studies quantified toxin suppression by measuring mRNA targets in culture media incubated with clindamycin concentrations as low as 1/8 MIC also showed significant reduction in PVL expression.16,17 One study utilized a hollow fiber in vitro model which is a two compartment pharmacokinetic/pharmacodynamics model that optimizes drug delivery and allows for simulation of sequestered infections. Clindamycin was then introduced to the model for incubation at a level that simulated the pharmacokinetics of the standard treatment dose of various antibiotics. This study then evaluated mRNA levels for gene expression of various toxins. Clindamycin at exposures simulating 600 mg every 8 hours demonstrated a significant downtrend in PVL toxin gene expression over 48 hours of incubation.16 

Linezolid is an oxazolidinone antibiotic which inhibits bacterial growth by disrupting the initiation process of protein synthesis and creates a bacteriostatic effect. Linezolid is a much newer antibiotic compared to clindamycin, thus there is less evidence supporting its use in toxin suppression. The previously mentioned study utilizing a hollow fiber in vitro model found linezolid dosed at 600mg every 12 hours to be effective at suppressing PVL gene expression for up to 24 hours.16 Two studies showed a reduction in PVL gene expression with linezolid and another study showed a decrease in direct PVL toxin quantity.14,16,17 Another study evaluated PVL toxin levels with subinhibitory concentrations of linezolid found that linezolid induced a concentration-dependent decrease in PVL level starting at concentrations as low as 1/8 or 1/4 MIC.15 

In Summary…

In vitro data supports the ability of both clindamycin and linezolid to suppress the production of PVL toxin in CA-MRSA isolates. The clinical utility of this information is still an area of future research. The association of PVL toxin with virulence of CA-MRSA has only been well established for necrotizing pneumonia and not for other types of PVL producing CA-MRSA infections. Clinical guidelines for MRSA treatment do not yet recommend the routine use of these antimicrobials for the purpose of toxin suppression. These antimicrobials carry their own risk of adverse events and should only be considered for use by experts in certain clinical scenarios. In vitro data also shows that subinhibitory concentrations of these drugs can inhibit toxin production; however, dosing regimens aimed to achieve these MICs in the site of infection in vivo have yet to be evaluated.

References

1. Chambers HF. Community-associated MRSA–resistance and virulence converge. N Engl J Med. 2005;352(14):1485-1487. doi:10.1056/NEJMe058023 

2. Francis JS, Doherty MC, Lopatin U, et al. Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis. 2005;40(1):100-107. doi:10.1086/427148 

3. Hageman JC, Uyeki TM, Francis JS, et al. Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerg Infect Dis. 2006;12(6):894-899. doi:10.3201/eid1206.051141 

4. Brown EL, Dumitrescu O, Thomas D, et al. The Panton-Valentine leukocidin vaccine protects mice against lung and skin infections caused by Staphylococcus aureus USA300. Clin Microbiol Infect. 2009;15(2):156-164. doi:10.1111/j.1469-0691.2008.02648.x 

5. Voyich JM, Otto M, Mathema B, et al. Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease?. J Infect Dis. 2006;194(12):1761-1770. doi:10.1086/509506 

6. Bubeck Wardenburg J, Bae T, Otto M, Deleo FR, Schneewind O. Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia. Nat Med. 2007;13(12):1405-1406. doi:10.1038/nm1207-1405 

7. Bubeck Wardenburg J, Palazzolo-Ballance AM, Otto M, Schneewind O, DeLeo FR. Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease. J Infect Dis. 2008;198(8):1166-1170. doi:10.1086/592053 

8. Bubeck Wardenburg J, Palazzolo-Ballance AM, Otto M, Schneewind O, DeLeo FR. Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease. J Infect Dis. 2008;198(8):1166-1170. doi:10.1086/592053 

9. Diep BA, Chan L, Tattevin P, et al. Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury. Proc Natl Acad Sci U S A. 2010;107(12):5587-5592. doi:10.1073/pnas.0912403107 

10. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67. doi:10.1164/rccm.201908-1581ST 

11. Liu C, Bayer A, Cosgrove SE, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children, Clinical Infectious Diseases, Volume 52, Issue 3, 1 February 2011, Pages e18–e55, https://doi.org/10.1093/cid/ciq146 

12. Hodille E, Badiou C, Bouveyron C, et al. Clindamycin suppresses virulence expression in inducible clindamycin-resistant Staphylococcus aureus strains. Ann Clin Microbiol Antimicrob. 2018;17(1):38. Published 2018 Oct 20. doi:10.1186/s12941-018-0291-8 

13. Herbert S, Barry P, Novick RP. Subinhibitory clindamycin differentially inhibits transcription of exoprotein genes in Staphylococcus aureus. Infect Immun. 2001;69(5):2996-3003. doi:10.1128/IAI.69.5.2996-3003.2001 

14. Stevens DL, Ma Y, Salmi DB, McIndoo E, Wallace RJ, Bryant AE. Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus. J Infect Dis. 2007;195(2):202-211. doi:10.1086/510396 

15. Dumitrescu O, Boisset S, Badiou C, et al. Effect of antibiotics on Staphylococcus aureus producing Panton-Valentine leukocidin. Antimicrob Agents Chemother. 2007;51(4):1515-1519. doi:10.1128/AAC.01201-06 

16. Pichereau S, Pantrangi M, Couet W, et al. Simulated antibiotic exposures in an in vitro hollow-fiber infection model influence toxin gene expression and production in community-associated methicillin-resistant Staphylococcus aureus strain MW2. Antimicrob Agents Chemother. 2012;56(1):140-147. doi:10.1128/AAC.05113-11 

17. Otto MP, Martin E, Badiou C, et al. Effects of subinhibitory concentrations of antibiotics on virulence factor expression by community-acquired methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2013;68(7):1524-1532. doi:10.1093/jac/dkt073 

UNMC ID is Looking for an Academic HIV Physician!

The Division of Infectious Diseases at the University of Nebraska Medical Center in Omaha, NE is looking to add an ID physician to join our well-established HIV team recognized for providing expert care locally, regionally, and nationally. Enjoy a varied inpatient and outpatient practice mix as part of our patient-centered team. Expect to treat a broad pathology with varied complexity in this position. If you are looking for a position in a robust HIV Program that offers you the ability to provide comprehensive care to a diverse patient population, look no further. Work with phenomenal physicians, nurse practitioners, pharmacists, nurses, social workers, case managers, and exceptional support staff.

UNMC ID Clinic Physicians

Pictured from left to right: Susan Swindells, MBBS; Nada Fadul, MD; Jasmine Marcelin, MD; Sara Bares, MD.

These are just 4 members of the larger UNMC HIV team. Check them out here!

This position also includes opportunities to initiate and participate in research activities and engage in the training of fellows, residents, medical students and other interprofessional students.  

Know the perfect person for this opportunity? Please spread the word via twitter or with the following application links: HEC, IDSA.

Publication Alert: Leveraging a Preexisting Global Infectious Disease Network for Local Decision Making During a Pandemic

The content below was provided by Jocelyn Herstein, an assistant professor at UNMC and Director of International Partnerships and Programs with the National Emerging Special Pathogens Training and Education Center. She led a recently published study, collaborating with UNMC ID faculty Drs. Angela Hewlett and James Lawler. 

What prompted this study?

Emerging infectious disease events require a rapid response from health systems; however, evidence-based consensus guidelines are generally absent early in emergency health events.

What does the GIDPN do?

In 2017, the Global Infectious Disease Preparedness Network (GIDPN) was formed by 5 high-level isolation units spanning 3 continents. In the early weeks of the COVID-19 pandemic, when information on the novel disease was frequently evolving and evidence-based guidelines were absent, the GIDPN was leveraged to rapidly exchange information, approaches, and experiences between the five units.

What is the take home message?

The networking facilitated by GIDPN allowed for rapid epidemiological and clinical decision-making in a local context. Shared knowledge led to earlier adoption of some treatment modalities as compared to most peer institutions and to implementation of protocols prior to incorporation into national guidelines. Networking of these specialized high-level isolation units have a role in enhancing preparedness for and response to future epidemics/pandemics. 

Jocelyn Herstein, PhD, MPH pictured left, led this project. She is assistant professor at UNMC and Director of International Partnerships and Programs with the National Emerging Special Pathogens Training and Education Center.

Read the full article here.

Citation: Herstein JJ, Lowe JJ, Wolf T, Vasoo S, Leo YS, Chin BS, Shen Y, Hewlett AL, Lawler JV. Leveraging a Preexisting Global Infectious Disease Network for Local Decision Making During a Pandemic. Clin Infect Dis. 2022 Mar 1;74(4):729-733. doi: 10.1093/cid/ciab660. PMID: 34318871; PMCID: PMC8406886.

Things ID Docs Read: An ID Perspective on the Safety of Sushi

Freezing seafood before preparation of sushi is recommended for elimination of certain parasites, but many worry about ruining the taste. Is there any evidence for lower quality in previously frozen seafood? Iwata et. al. investigates.

What does clinical infectious disease research have to offer the culinary world? The answer involves sushi, a freezer, and “a randomized double-blind trial with sensory evaluation using discrimination testing”.

In a recent article published in the journal Clinical Infectious Diseases, Kentaro Iwata and others aimed to disprove the notion that previously frozen seafood is less palatable than fresh seafood when prepared into sushi. Using 120 medical student volunteers and a recruited sushi chef, this group conducted a double-blind taste test of fresh and previously-frozen sushi ingredients. They found that participants were unable to distinguish between the two types of sushi.

This work may help dispel the belief that frozen mackerel and squid tastes worse than fresh fish. This is an important step towards the prevention of gastric anisakidosis caused by a parasite commonly found in fresh seafood. This infection, while usually self-limited and not life threatening, presents with excruciating stomach pain. In fact, the European Union requires and United States FDA recommends freezing these fish before preparation, effectively removing the risk of infection.

Read the full article here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392844/

Read more about foodborne zoonoses endemic in Asian countries here: https://academic.oup.com/cid/article/41/9/1297/278196?login=true

UNMC ID at #SHEASpring2022 – Where to Find Us!

The SHEA Spring conference starts tomorrow; here is your guide on where to find UNMC ID throughout the conference!

Invited Training Course Workshop Lectures

Tuesday, April 12th from 10:00am – 10:15am: SHEA/CDC Training Course in Healthcare Epidemiology as presented by our own Kari Simonsen.

Tuesday, April 12th from 2:45pm-3:15pm: Case Studies in Pediatric Infection Control (panel discussion) also with Kari Simonsen (among others).

Dr. Simonsen is also one of the session co-chairs of the SHEA/CDC Training Course in Healthcare Epidemiology!

Invited Lectures in Main Conference

Wednesday, April 13th from 10:00am-12:00pm: Unlocking JEDI Status in the Antimicrobial Stewardship Workforce presented by Jasmine R Marcelin (in session Diversity, Equity, Inclusion, and Access in Antimicrobial Stewardship, Hospital Epidemiology and The Public Health Workforce)

Thursday, April 14th from 2:45 PM – 4:00 PM: Don’t just Publish a Paper – #SoMe Your Story presented by Jasmine R Marcelin (in session Getting your message out to the masses: Understanding the promise and pitfalls of various dissemination methods)

Oral Abstract Presentations

Thursday, April 14th from 8:00am-9:30am: Nosocomial Outbreak of Delta Variant SARS-CoV-2 on a Liver Transplant Unit: A Complex Epidemiologic and Genomic Investigation by 2nd year UNMD ID Fellow Jonathan Ryder (R) and co-authored/mentored by Trevor Van Schooneveld (L). Other authors on this work include Baha Abdalhamid, Macy Wood, Rick Starlin, Gayle Gillett, Teresa Balfour, Libby Pflueger, and Mark E. Rupp.

Follow the conference on Twitter using the hashtag #SHEASpring2022 for meeting updates & highlights.

#PharmToExamTable: What is the rationale behind dosing frequency of cefadroxil for treatment of MSSA infections?

A #PharmToExamTable question about cephalosporin use, answered by Ken Chen, PharmD, a 2021 Graduate of UNMC College of Pharmacy.

(Reviewed by Andrew Watkins, PharmD)

Cefadroxil, a semisynthetic oral first-generation cephalosporin, has been available for over 40 years, with a patent in 1967 and approval for medical use in 1978. It works by inhibiting bacterial cell wall synthesis via binding to one or more of the penicillin-binding proteins (PBPs), which in turn inhibits the final step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. The major adverse effects of cefadroxil involve the gastrointestinal tract (dyspepsia, nausea and vomiting, diarrhea) and skin (hypersensitivity reactions in the form of rash, urticaria, angioedema, and pruritus) (1).

Cefadroxil vs. Cephalexin

In terms of pharmacokinetics, cefadroxil is similar to cephalexin, a widely-used first-generation oral cephalosporin. Both drugs are readily absorbed after oral administration and primarily excreted unchanged in the urine. The usual dosing of cefadroxil in patients with normal renal function is 1 to 2 g daily in a single or divided dose compared to cephalexin which may dosed at 250 mg to 1 g every 6 hours. In patients with a urinary tract infection (UTI), cefadroxil and cephalexin may be given as low as once and twice daily, respectively (1,2). The decreased frequency of administration of cephalexin results in significant improvement of patient’s adherence to the medication. With one study noting up to a 30% absolute increase in adherence associated with twice-daily dosing, compared with more frequent administration (3).

Cefadroxil may be administered less frequently compared with cephalexin due to its elimination half-life (t1/2). The serum t1/2 of cefadroxil ranges from 1.1 to 2 hours in adults with normal renal function (4-10). Barbhaiya et al. examined the pharmacokinetics of cefadroxil and cephalexin following single oral doses of either 250, 500 or 1000 mg to a total of 36 healthy volunteers (4). Although values for the peak concentrations (Cmax) for cefadroxil were lower than that of cephalexin, the elimination t1/2 of cefadroxil (~2 hours) was significantly longer than that of cephalexin (~1 hour). Hartstein et al. reported that after equivalent oral dosages, concentrations of cefadroxil in serum and urine were higher and more sustained than were those of cephalexin (11). The longer t1/2 results in a longer time period greater than MIC for cefadroxil compared with an equivalent dose of cephalexin. The cefadroxil concentration in
urine was maintained well above the MIC of all organisms tested for 12+ hours (11). The pharmacokinetic properties of cefadroxil are supportive of the development of clinical efficacy data which could indicate that cefadroxil could be administered at 12-hour intervals.

Can We Use Cefadroxil for MSSA Bacteremia?

Early oral stepdown therapy has been studied in patients with Methicillin-susceptible or Methicillin-resistant Staphylococcus aureus bacteremia who have achieved clinically stable status and received appropriate intravenous antibiotics for 7 to 10 days. One retrospective cohort study (n=100) evaluating the safety of early oral antibiotic switch (prior to 14 days) for low-risk Methicillin-susceptible Staphylococcus aureus bacteremia utilized beta-lactam therapy as the main (72/84, 86%) oral drug of choice (13). Of the 72 patients who received oral beta-lactam therapy, only 7 patients used cephalexin, while 60 patients used flucloxacillin and 5 patients used other beta-lactams. The study was unable to identify a statistical difference between early switch to oral beta-lactam therapy in terms of blood culture relapse, readmission related to Staphylococcus bacteremia, or mortality (13).

Conclusions

Due to the longer elimination t1/2 of cefadroxil compared with cephalexin, cefadroxil can be given less frequently. There is insufficient information to definitively comment on the practice of using oral beta-lactam as a stepdown therapy in patients with Staphylococcus aureus bacteremia.

References

  1. Cefadroxil [package insert]. Hyderabad, India: Aurobindo Pharma Limited; 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7bb90096-14d3-400e-94d3-048bff6b1292.
  2. Cefadroxil. In: Lexi-Drugs Online. Hudson (OH): Lexi-Comp, Inc.; [updated 4/6/21; accessed 4/25/21]. https://online-lexi-com/lco/action/doc/retrieve/docid/patch_f/6549?cesid=0L41TfVcSAf&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dcefadroxil%26t%3Dname%26va%3Dcefadroxil.
  3. Sclar DA, Tartaglione TA, Fine MJ. Overview of issues related to medical compliance with implications for the outpatient management of infectious diseases. Infect Agents Dis. 1994;3(5):266-273.
  4. Barbhaiya RH. A pharmacokinetic comparison of cefadroxil and cephalexin after administration of 250, 500 and 1000 mg solution doses. Biopharm Drug Dispos. 1996;17(4):319-330.
  5. Pfeffer M, Jackson A, Ximenes J, et al. Comparative human oral clinical pharmacology of cefadroxil, cephalexin, and cephradine. Antimicrob Agents Chemother. 1977;11:331-338.
  6. Marino EL, Dominguez-Gil A. Influence of dose on the pharmacokinetics of cefadroxil. Eur J Clin Pharmacol. 1980;18:505-509.
  7. Humbert G, Leroy A, Fillastre JP, et al. Pharmacokinetics of cefadroxil in normal subjects and in patients with renal insufficiency. Infection.1980; 8(Suppl 5):S598-602.
  8. Lode H, Stahlmann R, Koeppe P. Comparative pharmacokinetics of cephalexin, cefaclor, cefadroxil, and CGP 9000. Antimicrob Agents Chemother. 1979;16:1-6.
  9. La Rosa F, Ripa S, Prenna M, et al. Pharmacokinetics of cefadroxil after oral administration in humans. Antimicrob Agents Chemother. 1982;21:320-322.
  10. Welling PG, Selen A, Pearson JG, et al. A pharmacokinetic comparison of cephalexin and cefadroxil using HPLC assay procedures. Biopharm Drug Dispos. 1985;6:147-157.
  11. Hartstein AI, Patrick KE, Jones SR, Miller MJ, Bryant RE. Comparison of pharmacological and antimicrobial properties of cefadroxil and cephalexin. Antimicrob Agents Chemother. 1977;12(1):93-97.
  12. Dagher M, Fowler VG Jr, Wright PW, Staub MB. A Narrative Review of Early Oral Stepdown Therapy for the Treatment of Uncomplicated Staphylococcus aureus Bacteremia: Yay or Nay?. Open Forum Infect Dis. 2020;7(6):ofaa151.
  13. Bupha-Intr O, Blackmore T, Bloomfield M. Efficacy of Early Oral Switch with β-Lactams for Low-Risk Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother. 2020;64(7):e02345-19.
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HIV Enhanced Medical Education Track Students: Projects and Match Day Successes

The UNMC College of Medicine offers a unique Enhanced Medical Education Track (EMET) program which provides an opportunity for medical students to delve into particular disciplines of interest in the field of medicine throughout their four-year degree program. Track students attend seminars, preceptorships and complete a research project culminating in a poster or conference presentation.

Last week, on the eve of their Match Day, two of our M4 EMET Students, Rohan Khazanchi and Samantha Cox (under the mentorship of Drs. Jasmine Marcelin, Nada Fadul, and Sara Bares) presented their Capstone Projects at UNMC College of Medicine.

On March 18, after years of hard work, months of interviews, weeks of decision, and the most anxiety-filled week of their lives, they found out where they will be spending the next few years of their lives as newly minted doctors.

Over the last four years, Rohan has developed a research focus examining the intersections of race, place, and health. His M.D. Honors Thesis reflects a snapshot of these efforts. He leveraged area-based measures to investigate structural inequities and applied novel social epidemiologic tools to measure and explore disparate outcomes. Lastly, he discussed concrete implications for clinicians, researchers, and policymakers alike. Rohan will be continuing his medical training with residency training in Med/Peds at Brigham & Women’s Hospital affiliated with Harvard University. Read more about his work on Twitter.

Samantha’s project was a literature review of the existing research surrounding the relationship between HIV-related stigma and ART adherence. This relationship has become increasingly important as we know that current ART regimens are highly effective with minimal side effects, yet we still have patients with HIV who have unsuppressed viral loads. She found a paucity of overall research meeting her criteria and some significant variability with regards to how researchers measure and define both stigma and medication adherence. Her hope is that future research would use consistent, validated measurements of these variables and also test out interventions to mitigate internal HIV-stigma of patients and enacted stigma by healthcare professionals and the general population. Samantha will continue her medical training with residency training in Emergency Medicine in St. Paul, MN. We wish her all the best!

Harrison Greene, another HIV EMET medical student, matched into psychiatry residency here at UNMC. We are excited to keep seeing him around during his training!

Each year, our UNMC HIV clinic takes two medical students into the EMET track, and we look forward to working with them over the course of their undergraduate medical training to immerse them in HIV care and Infectious Diseases. We will soon be announcing our new M1 EMET students, who will start working with us over the coming summer.

Congratulations again to Rohan, Harrison, and Samantha, we are proud of you! And congratulations to all M4s out there who found out where they matched last week!

More information about the EMET program can be found here.

Introducing our new Assistant Editor of Digital Content and Scholarship – Zachary Van Roy

“We are thrilled to introduce our new Assistant Editor of Digital Content and Scholarship, Zachary Van Roy! You may have already seen one of his posts, as he’s hit the ground running. Zach is going to be curating and creating new digital content for our blog, and collaborating with us on exciting new #SoMe Scholarship. Look out for this bright young star as he makes his way through the infectious diseases and social media worlds!”

– Jasmine Marcelin and Kelly Cawcutt, Co-Directors of Digital Innovation and Social Media Strategy, UNMC ID

Tell us a little about yourself:

I grew up right here in Omaha and graduated from the University of Nebraska-Lincoln where I studied mathematics, microbiology, and biochemistry. Now I am back in Omaha continuing my education at UNMC and I am interested in a career as an ID physician scientist.

What are you doing now?

I am a fourth-year MD-PhD student at UNMC currently working on my PhD in Dr. Tammy Kielian’s laboratory. I am working on understanding the epigenetic changes that allow our immune cells to fight infections, specifically Staphylococcus aureus craniotomy infection.

Why were you interested in working with the ID blog?

Infectious disease is a fascinating field, and I don’t think it traditionally gets the exposure it deserves. I got my first taste of ID while working in a plant pathology laboratory with the USDA and have been hooked ever since. When I heard about UNMC’s ID blog, I thought it was great that there was a centralized way to celebrate new faculty and work from ID researchers and talk about the wild world that is infection science. I am just excited to be a part of the ID conversation!

Tell us something about yourself that is unrelated to medicine.

I’m a huge fan of anything music-related, so I spend a lot of my free time either playing or listening to music. I also recently adopted a golden retriever who keeps me pretty busy.

Publication Alert: Antiretroviral Refill Histories as a Predictor of Future Human Immunodeficiency Virus Viremia

The content below was provided by Darryl Sokpa, ’22 PharmD/MBA candidate at UNMC College of Pharmacy. He led a recently published study, collaborating with UNMC ID faculty Drs. Sara Bares and Nada Fadul, and mentored by UNMC ID pharmacist faculty Dr. Joshua Havens.

What prompted this study?

Adherence to antiretroviral therapy (ART) remains the cornerstone of treatment for HIV infection.  Many adherence metrics including subjective reporting, assessment of drug concentrations in dried blood spots (DBS)/hair/urine, novel technologies such as medication event monitoring systems, and the quantification of prescription refill histories as a percentage of days covered (PDC), have been evaluated in other studies.  While each of these adherence metrics has its own set of positive and negative attributes, PDC is arguable the easiest to collect, encompassing of all antiretrovirals, and can be used in real-time clinical decision-making. 

Our colleagues, Byrd et al, have explored using PDCs to evaluate association with viral suppression and to identify minimum PDC thresholds for current viral suppression both in aggregate and by ART regimen type.  We wanted to evaluate the use of PDC as a measure to assess future viral failure and to identify an associated PDC threshold level.  Additionally, we aimed to find predictive factors for low adherence levels under the identified PDC threshold level.

What are the key findings?

Our analysis found PDC was associated future viral failure in our cohort of 867 participants contributing to 1923 matched pairs (annual PDC matched to first reported HIV RNA in subsequent year).  PDC ≤52% was identified as a threshold level predictive of future HIV viremia in our analysis.  Sub-groups with higher odds of a PDC ≤52% were Black race, people experiencing homelessness, those with government-based insurance or uninsured, and those not in a committed relationship. 

What is the clinical take home message?

Our findings suggest PDC may be a useful clinical tool to identify patients at risk of future viral failure.  Additionally, our results may help clinicians better understand adherence trends to make better real-time clinical decisions and identify patients that may benefit from adherence support interventions and/or resistance testing.  Further, in conjunction with the findings of Byrd et al, we now have a key adherence zone bordered by the identified PDC thresholds (52-82%) to be further evaluated for long-term HIV outcomes.

Lastly, while the current literature using PDC as an adherence marker is encouraging, it is important to recognize the limitations of PDC values.  Most notably, PDC is still an imperfect adherence metric because it only represents pharmacy ART dispensations and not actual ingestion.   

Darryl Sokpa, pictured left, led this project. He is a ’22 PharmD/MBA candidate at UNMC College of Pharmacy.

Read the full article here.

Citation: Sokpa D, Lyden E, Fadul N, Bares SH, Havens JP. Antiretroviral Refill Histories as a Predictor of Future Human Immunodeficiency Virus Viremia. Open Forum Infect Dis. 2022 Jan 28;9(3):ofac024. doi: 10.1093/ofid/ofac024. PMID: 35187193; PMCID: PMC8849282.

#PharmToExamTable: Are we correctly dosing β-lactam antibiotics?

A #PharmToExamTable question about antibiotic treatment, answered by Jeremy Tigh, PharmD, an ID pharmacy resident at UNMC

(Reviewed by Andrew Watkins, PharmD)


In a recent popular publication, Crass et al. ask the question: are we jumping the gun on renal dosing of antibiotics? In this review I expand upon Crass’s question, with a focus on β-lactams.

β-lactams, Dosing Strategies, and Clinical Trials

β-lactams are one of the most commonly prescribed antibiotic drug classes with numerous clinical indications for gram-positive and gram-negative infections. Penicillins, cephalosporins, and carbapenems all share common s structural aspects that bind to penicillin binding proteins, inhibiting the cross linking of peptides in the bacterial cell wall, resulting in bactericidal action. Efficacy parameters are described as the percentage of time of the dosing interval in which the free serum antibiotic concentration remains above the minimum inhibitory concentration (MIC). The value needed for bactericidal activity varies, but generally the goal is 40-70%; however, clinical data suggests that optimal rates of clinical cure and bacteriological eradication (protects against regrowth and subsequent development of resistance) are achieved with time above MIC of 100% (1).

Early Antibiotic Therapy and Acute Kidney Injury

Acute kidney injury (AKI) is common in patients presenting with infectious diseases resulting in dosage adjustment per drug labeling for many first line antibiotics. Crass et al. hypothesized that this dosage reduction is likely unnecessary in many patients as AKI can be transient and that by dose-adjusting so early in therapy, important patient outcomes may be impacted due to decreased drug exposure (3). In their retrospective study looking at more than 18,500 patient encounters they were able to provide evidence to support their hypothesis. AKI was common with an overall rate of approximately 1 in 5 of their population. When they restricted their analysis to patients with clinically meaningful renal dysfunction (likely warranting dose adjustment) up to 38% of those cases may have qualified. Additionally, they showed that 57% of those patients had resolution of their kidney injury by 48 hours and that there was a higher probability that patients with AKI on admission would have recovery rather than persistence of the AKI (3). One possible explanation for this dynamic renal function may be due to inaccuracies in the way that we measure and estimate a patient’s clearance, as serum creatinine is dynamic and variable. The authors suggest that delaying dose adjustment on initiation of therapy for β-lactam antibiotics may enhance meeting pharmacodynamic targets during crucial early therapy, but this must be balanced with the risk of toxicity. Limitations of their study include that antibiotic dosing and patient outcomes were not evaluated, making it difficult to know whether or not this actually affects patient outcomes.

Critically Ill Patients

Intensive care unit (ICU) patients are usually excluded from dose finding studies as pharmacokinetics and drug exposure are often significantly altered in this population (4). Because of this, utilizing standard dosing regimens for β-lactams may make it difficult to achieve optimal exposure. A recently published study by Abdulla et al. looked at patients treated with a variety of β-lactams and subsequent drug levels and attainment of pharmacodynamics goals (.4) The study included 147 patients, of which 63.3% met a goal of time above MIC at 100%. When analyzing time above 4 times the MIC (a suggested optimal concentration), only 36.7% met the goal. They identified male gender, a high BMI, and an eGFR >90 ml/min as risk factors for not obtaining goal PD parameters. Another study performed by Wong et al. support these findings (5) In a similar population they analyzed the same PD goals, but also analyzed time that drug concentration was 10 times above MIC, a subjective surrogate for toxicity. Out of 330 patients analyzed, a similar number of patients met PD goals as compared to Abdulla et al., but 17.3% of patients were indicated to have dosage reductions with measured high levels, emphasizing the risk of excessive drug exposure. Failure to obtain target values was not independently associated with negative clinical outcomes, making it difficult to support the hypothesis that non-target obtainment would lead to worse clinical outcomes. The complexity and dynamic nature of ICU patients makes associating clinical variables and risk of not obtaining target PK/PD goals difficult to apply without therapeutic drug monitoring. Currently, therapeutic drug monitoring for β-lactams is not widely used in clinical practice. Lack of guidelines, long turnaround times, and limited laboratory access are barriers to its implementation (4,5).

Conclusions

It is important to consider the limitations of estimating renal function and applying renal dosage adjustment to dynamic patients. Prospective studies are needed to establish causal links between antibiotic doses, renal dysfunction and enhancement (ARC), and patient outcomes in both acute and critically ill patients before therapeutic drug monitoring of β-lactams will be accepted as a useful tool in optimizing therapy.

References

  1. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26(1):1-10; quiz 11-12.
  2. Zhang L, Xu N, Xiao S, et al. Regulatory perspectives on designing pharmacokinetic studies and optimizing labeling recommendations for patients with chronic kidney disease. Journal of clinical pharmacology. 2012;52(1 Suppl):79s-90s.
  3. Crass RL, Rodvold KA, Mueller BA, Pai MP. Renal Dosing of Antibiotics: Are We Jumping the Gun? Clin Infect Dis. 2019;68(9):1596-1602.
  4. Abdulla A, Dijkstra A, Hunfeld NGM, et al. Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT). Critical care (London, England). 2020;24(1):558.
  5. Wong G, Briscoe S, McWhinney B, et al. Therapeutic drug monitoring of β-lactam antibiotics in the critically ill: direct measurement of unbound drug concentrations to achieve appropriate drug exposures. Journal of Antimicrobial Chemotherapy. 2018;73(11):3087-3094.
  6. Boschung-Pasquier L, Atkinson A, Kastner LK, et al. Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2020;26(3):333-339.
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