Division of Infectious Diseases

A #PharmToExamTable question about adverse vancomycin reactions, answered by Quynh Tran, PharmD, a Graduate of UNMC College of Pharmacy.

(Reviewed by Andrew Watkins, PharmD)

Vancomycin is a glycopeptide antibiotic frequently utilized to treat infections caused by resistant gram-positive organisms such as methicillin resistant Staphylococcus aureus (MRSA).¹  Due to widespread vancomycin use, resistant organisms such as vancomycin-resistant Enterococcus (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA) have been a growing problem within healthcare facilities. Thus, the glycopeptide family of antibiotics has since expanded to help overcome these resistances and offer alternate treatment options. New lipoglycopeptides antibiotics such as telavancin, oritavancin, and dalbavancin have been utilized for the treatment of resistant gram-positive organisms, particularly MRSA and Enterococcusfaecium. Clinical cross-reactivity between glycopeptides remains controversial, with varied reports suggesting possible immunological cross-reactivity. This review will focus on potential cross-reactivities between vancomycin and lipoglycopeptides. 

What are Glycopeptide Antibiotics?

Glycopeptides are bactericidal cyclic non-ribosomal peptides produced by various filamentous actinomycetes. They facilitate inhibition of cell wall synthesis by impeding transglycosylation & transpeptidation.² Vancomycin was one of the first glycopeptides discovered, and it can be used intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by most gram-positive organisms. Due to an increase in resistance to vancomycin, lipoglycopeptides (a class of antibiotics that have lipophilic side chains linked to glycopeptides) were developed. The three antibiotics in this class approved by the FDA are telavancin, dalbavancin, and oritavancin. All three antibiotics are approved for skin/soft tissue infections, and they can be used for gram-positive bacteria that are resistant to vancomycin. Another benefit of these antibiotics is their prolonged duration of action, allowing less frequent administration. While telavancin typically requires administration every 24 hours, dalbavancin can be administered as a once weekly injection for 1-2 doses depending on the infection.³ In theory, telavancin is most at risk of possible cross-reactivity as its glycopeptide core is vancomycin.⁴ Due to their benefit, the lipoglycopeptides have been used more frequently in clinical settings, but because of their structural similarities to vancomycin, it is important to understand their cross-reactivity with vancomycin to assist in safe use of these medications in patients with vancomycin allergy.

Adverse Vancomycin Reactions

Adverse drug reactions with vancomycin include both non-immune mediated reactions such as nephrotoxicity and non-immunoglobulin E (IgE) mediated mast cell reactions (i.e., red man syndrome) as well as immune-mediated reactions such as T-cell mediated severe cutaneous adverse reactions (i.e., drug reaction with eosinophilia and systemic symptoms (DRESS)).

Non-IgE mediated vancomycin hypersensitivity – red man syndrome – is typically characterized by a pruritic, erythematous rash that predominantly affects the face, neck, and trunk and is caused by mast cell degranulation.⁵ It is usually related to intravenous doses greater than 1000 mg with rapid administration under 60 minutes. Recurrence of red man syndrome can usually be managed by reducing the rate of infusion of vancomycin and/or premedication with antihistamines. A potential mechanism for this reaction is direct mast cell degranulation via the MAS-related G-protein coupled receptor X2 (MPGPRX2).⁶

On the other hand, patients might experience immune mediated hypersensitivity with vancomycin such as IgE mediated reactivity (true anaphylaxis) and DRESS. There is no clear way to distinguish red man syndrome from IgE mediated reactions in patients receiving vancomycin; thus, IgE mediated hypersensitivity should be suspected in patients who have severe multiorgan involvement suggesting anaphylaxis or who fail red man protocols for intravenous administration.⁷ DRESS most frequently occurs during vancomycin therapy with a median of 18 days after start of therapy. Its clinical presentation includes widespread rash, fever, facial edema, increase in white blood cells, and involvement of internal organs. Konvinse et al. reviewed a cohort study of 23 patients with vancomycin DRESS and showed that over 80% of these patients carried the HLA-A*32:-01 allele compared to the 0 in 46 vancomycin tolerant controls.⁸

What About Lipoglycopeptide Cross-reactivity?

A recent study by Nakkam et al. looking at DRESS cross-reactivity among vancomycin, teicoplanin, dalbavancin, telavancin showed that patients with a history of previous vancomycin-induced DRESS had potential risk of cross-reactivity between vancomycin, teicoplanin, and telavancin, but lower risk of cross-reactivity with dalbavancin. This result aids in decision making in the future and reassures the use of dalbavancin in vancomycin-allergic patients^.9

In conclusion…

Telavancin has higher potential cross-reactivity with vancomycin compared to dalbavancin and oritavancin due to its similarity in the core structure with vancomycin. However, further studies are needed to understand more about the cross-reactivity mechanism. Future studies on an association of vancomycin-induced DRESS with HLA-A*32:-01 could be important in understanding cross-reactivity for immune mediated reactions.

References

1. Griffith RS. Vancomycin use: an historical review. J Antimicrobial Chemotherapy 1984; 14: 1-5.
2. Zhanel GG, Calic D, Schweizer F, et al. New lipoglycopeptides: a comparative review of dalbavancin, oritavancin, and telavancin. Drugs 2010; 70: 859-886.
3. Kahne D, Leimkuhler C, Lu W, Walsh C. Glycopeptide and Lipoglycopeptide antibiotics. Chemical Reviews 2005; 105: 425-448.
4. Gelfand MS, Cleveland KO, Memon KA. Detection of vancomycin levels in patients receiving telavancin but not vancomycin. J Antimicrobial Chemotherapy 2012; 67: 508-509.
5. Sivagnanam S, Deleu D. Red man syndrome. Critical Care 2003; 7:119.
6. Azimi E, Reddy VB, Lerner EA. Brief communication: MRGPRX2, atopic dermatitis and red man syndrome. Itch (Phila) 2017; 2:e5.
7. Minhas JS, Wickner PG, Long AA, et al. Immune-mediated reactions to vancomycin. Ann Allergy, Asthma Immunol 2016; 116:544-553.
8. Konvinse KC, Trubiano JA, Pavlos R, et al. HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms. J Allergy Clin Immunol 2019; 144:183-192.
9. Nakkam N, Gibson A, Mouhtouris E, Konvinse KC, et al. Cross-reactivity between vancomycin, teicoplanin, and telavancin in patients with HLA-A*32:01 positive vancomycin induced DRESS sharing an HLA class Ii haplotype. Journal of Allergy and Clinical Immunology 2020.

A #PharmToExamTable question about fluconazole dosing, answered by Brady Caverzagie, PharmD, a Graduate of UNMC College of Pharmacy.

(Reviewed by Andrew Watkins, PharmD)

Cryptococcus spp. are fungal pathogens found in the soil and pigeon droppings. Usually, Cryptococcus spp. do not cause severe or life-threatening symptoms in immunocompetent patients; however, in immunocompromised patients, cryptococcal infections can cause serious complications.  Patients who are HIV positive with high viral loads and low CD4 cell counts are especially susceptible to infection with cryptococcal species, which can disseminate throughout the body, including the central nervous system (CNS).  Once in the CNS, patients often have a classic meningitis-like presentation including headache, stiff neck, fever, and photophobia. Standard treatment for cryptococcal meningitis in the setting of HIV includes long courses of antifungals, relief of intracranial pressure, and supportive care.¹

Antifungal treatment includes three different phases: induction, consolidation, and maintenance. The 2010 Infectious Disease Society of America (IDSA) guidelines for cryptococcal meningitis for HIV-infected individuals recommends induction therapy with liposomal amphotericin at a dose of 3-4 mg/kg intravenously per day along with flucytosine 100 mg/kg orally per day in four divided doses for at least two weeks. Induction therapy continues for two weeks or until clearance of Cryptococcus from the cerebrospinal fluid, whichever comes last. Consolidation therapy follows the induction period and consists of 400 mg per day of fluconazole by mouth for a minimum of eight weeks. The last phase is maintenance therapy which is generally 200 mg per day of fluconazole by mouth for 6-12 months.²

There is not an established fluconazole breakpoint for Cryptococcus spp., from the Clinical and Laboratory Standards Institute (CLSI), making it difficult to determine if the recommended treatment is optimal in the setting of elevated minimum inhibitory concentrations (MIC).^3,4 Although the most common fluconazole MIC for Cryptococcus spp. Is 4 mg/L, a systematic review showed the median increase from 4 µg/mL in 2000-2012 to 8 µg/mL in 2014-2018.⁵ Additionally, worse patient outcomes and treatment failures have been observed in patients with cryptococcal isolates that have higher fluconazole MICs.⁶ The recent decrease in susceptibility to fluconazole in cryptococcal species is forcing a reevaluation of the appropriateness of 400mg per day of fluconazole in consolidation therapy for cryptococcal meningitis.^4,5  

Fluconazole works by inhibiting the fungal CYP P450 dependent enzyme lanosterol 14-α-demethylase, which converts lanosterol to ergosterol. Without ergosterol, the fungal cell membrane cannot function properly. Oral bioavailability of fluconazole is excellent at over 90%, making it a good option for long term outpatient therapy. While fluconazole distributes well to the urine and skin, with levels ~10x those seen in plasma, it distributes less well to the cerebrospinal fluid with levels 50-90% of those seen in plasma. The inhibition of human CYP enzymes (primarily CYP 3A4) leads to numerous drug interactions and careful monitoring of these interactions is important during therapy, especially in long courses of fluconazole used in cryptococcal meningitis.⁷

In the face of increasing MICs and an infection in an area of the body with lower drug penetration, the question becomes what dose will work for consolidation therapy in a patient with cryptococcal meningitis once they have completed induction therapy? Based on a model created to investigate fluconazole use for all phases of cryptococcal therapy, 400 mg daily would reach therapeutic levels of >100 AUC:MIC for 53% of isolates, 800 mg daily would reach therapeutic levels for 74% of isolates and 1200 mg would be effective for 83% of isolates.⁵ The data from the model can be reconfigured to demonstrate what dose can reasonably be expected to treat a particular isolate based on MIC (Table 1). The guideline driven 400 mg per day dose of fluconazole for consolidation may only be consistently effective for highly susceptible pathogens, leaving the rising incidence of resistant organisms to grow unchecked.

Table 1: Probability of achieving >100 AUC:MIC based on MIC and dose

Cryptococcal meningitis is a serious infection that needs to be adequately treated, and the MIC of cryptococcal isolates should be taken into consideration, particularly in immunocompromised patients. The guideline dosing for fluconazole consolidation treatment of 400mg daily is likely sufficient for cryptococcal isolates with an MIC of 2 mg/L, however fluconazole MICs among cryptococcal species have been increasing over the past two decades. To adequately reach therapeutic levels in patients with less susceptible organisms, doses of 800-1200mg per day could be necessary. Patients should be monitored carefully because tolerability of fluconazole may become a clinical issue at higher doses. Although limited evidence exists in these situations, an alternative agent may be necessary if MICs exceed 16 mg/L or patients become intolerant to fluconazole therapy.

References:

1. Dipiro JT, et al. Pharmacotherapy A Pathophysiological Approach. 11^th ed. McGraw-Hill 2019.
2. Perfect JR, et al. Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America, Clinical Infectious Diseases, Volume 50, Issue 3, 1 February 2010, Pages 291–322.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antifungal Susceptibility Testing of Yeasts. 1^st ed.  CLSI supplement M60. Wayne, PA: CLSI; 2017.
4. Bongomin F, et al. A systematic review of fluconazole resistance in clinical isolates of Cryptococcus species. Mycoses. 2018;61(5):290-297.
5. Chesdachai S, et al., Minimum Inhibitory Concentration Distribution of Fluconazole Against CryptococcusSpecies and the Fluconazole Exposure Prediction Model, Open Forum Infectious Diseases, Volume 6, Issue 10, October 2019.
6. Sai Cheon JW, McCormack J. Fluconazole resistance in cryptococcal disease: emerging or intrinsic?, Medical Mycology, Volume 51, Issue 3, April 2013, Pages 261–269.
7. Diflucan (fluconazole) [package insert] New York, NY: Pfizer Inc; September 2020.