September 2018 FAQs

What is the emerging pathogen Candida auris and what should pharmacists know about it?

Introduction

Invasive infections due to Candida species of fungi are a major cause of morbidity and mortality.^1,2 While at least 15 different Candida species are associated with human disease, the vast majority are attributable to the more common species, including C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei. Given the well-known epidemiology and burden of Candida infection, various guidances and considerable studies are available on the management of infection with these Candida species.

A relatively new species of Candida, C. auris, is a rapidly emerging fungal pathogen that has received considerable attention from clinicians and infection control agencies from multiple countries.^3,4 Because of its recent emergence, comparatively little is known about C. auris, and its optimal treatment is not established. C. auris is often multidrug-resistant (MDR), associated with high mortality, difficult to identify with standard methods, and has caused outbreaks in healthcare settings.⁵ Because of these concerns, the US Centers for Disease Control and Prevention (CDC) has offered recommendations on management, control, and prevention of C. auris and is encouraging US laboratories to notify CDC and state or local public health authorities of identified cases.^3,6,7 Given its rapid emergence and ongoing developments, this document reviews current recommendations for identification, management, and prevention of C. auris infection.

Epidemiology and risk factors

Candida auris was first identified as a novel species in 2009 in an isolate of external ear discharge of a patient in Japan.^5,8 In subsequent years, cases continued to be reported, and in April 2015, a cardiothoracic intensive care unit (ICU) in the United Kingdom (UK) first described a hospital outbreak of 50 cases of C. auris over 16 months in a single hospital.^5,9,10 Following these events, the CDC issued a clinical alert for US healthcare providers in June 2016 regarding the severity of C. auris and measures for its prevention, control, and reporting.¹¹

As of July 2018, C. auris has been reported in more than a dozen countries, including Africa, Asia, Europe, India, North America, and South America.^5,12 In the US, the CDC has tracked 340 confirmed cases of C. auris in 11 states, dating from the first report in 2013 up to June 30, 2018.^4,13,14 The largest numbers of cases have been reported in New York, New Jersey, and Illinois, which are proposed to be attributable to population density, interconnectedness of healthcare facilities, and/or increased surveillance.^4,14

Generally, risk factors for C. auris are similar to those for Candida species in general.¹³ These include immunosuppression, diabetes mellitus, central venous and urinary catheterization, mechanical ventilation, parenteral nutrition, receipt of surgery or broad-spectrum antimicrobials, and ICU or skilled nursing facility admission.^13,15,16 Notably, pre-term or low-birthweight infants, as well as elderly patients, are believed to be at higher risk of C. auris-associated mortality because of their weaker immune systems.¹⁵

Microbiology and identification

The pathogenicity of C. auris is severe, and is believed to be attributable to its production of phospholipase, proteinase, and biofilms that adhere to catheter material.^4,13  Mortality rates of patients with invasive C. auris infection have been estimated at greater than 1 in 3.¹⁷

Misidentification of C. auris has been reported and is a major concern of the CDC.^3,4,18-20 Some have proposed this may be due to the dearth of representative organisms in available datasets.⁴ C. auris has been misidentified as at least 9 different Candida species.⁴ Among these, some propose that clinicians be particularly alert for C. auris to be misidentified as C. haemulonii.

The CDC has recommended diagnostic devices that can differentiate C. auris from other Candida species, and has published a detailed algorithm to identify C. auris based on the phenotypic laboratory method and initial species identification.^21,22 Additionally, the Food and Drug Administration (FDA) approved in April 2018 the first test to identify C. auris.^17,23 Findings indicated the test is highly reliable, and its availability is anticipated to facilitate updates to organism databases to improve the ability to identify C. auris.

Resistance patterns and treatment options

C. auris has demonstrated resistance to all major classes of antifungal therapy.²⁴ C. auris is characteristically resistant to fluconazole, with an estimate rate of resistance in US isolates of 90%.²² Numerous in vitro and genomic analyses of international C. auris isolates have also documented resistance to other azoles, amphotericin B, echinocandins, and flucytosine, with some isolates exhibiting MDR.^24-28 Because of these concerning resistance patterns, the CDC recommends that all C. auris isolates undergo antifungal susceptibility testing.²² Some also propose that isolates that are resistant to azoles, echinocandins, or amphotericin B should also be tested for susceptibility to flucytosine, nystatin, and terbinafine.²⁴

The CDC has proposed C. auris minimum inhibitory concentration (MIC) breakpoints for amphotericin B, anidulafungin, caspofungin, micafungin, fluconazole, and voriconazole.²² However, these MIC breakpoints are tentative and based upon those for related Candida species until definitive C. auris-specific breakpoints are established. Therefore, clinicians should reassess these recommendations because future data may influence revisions to MIC breakpoints. Furthermore, in vitro studies have identified better activity with posaconazole and isavuconazole, which may also be assigned future MIC breakpoints.^{4,29 30}

Optimal treatment of C. auris is currently not established because of its propensity to be MDR.¹² As recommended by CDC, first-line empiric therapy comprises an echinocandin (Table 1), and therapy should be streamlined based on susceptibility reports.^6,12,24 Generally, both adults and children may be treated with caspofungin or micafungin; anidulafungin is also an option in adults, but is not approved for use in children. Doses of echinocandins for treatment of C. auris differ in that adults may receive fixed daily dosing, while pediatric dosing is based on weight or body surface area.

Because C. auris appears to quickly develop resistance to antifungal therapy, all patients should be monitored for clinical improvement, including subsequent cultures and susceptibility testing.⁶ Patients not responding to echinocandin therapy or who have persistent fungemia for > 5 days may be switched to treatment with liposomal amphotericin B (5 mg/kg daily). Other considerations and general management of C. auris should be followed per 2016 guidelines from the Infectious Diseases Society of America, and all patients with C. auris infection are highly recommended to receive consultation from an infectious disease specialist.^2,6

Novel agents that provide activity against C. auris are currently under investigation. These include the novel glucan synthase inhibitor ibrexafungerp (formerly SCY-078), the long-acting echinocandin rezafungin, and the glycosylphosphatidylinositol inhibitor APX001A.^31-37 These may soon expand treatment options of C. auris; the US FDA has granted qualified infections disease product and orphan drug statuses to all three agents, as well as fast-track status to ibrexafungerp and rezafungin.^32,38,39

Prevention and control

Numerous factors contribute to the ability of C. auris to persist in hospital environments. For example, C. auris can colonize the skin, and surveillance efforts have detected contamination of environmental surfaces and hands of healthcare workers.^5,40,41 Additionally, C. auris is thermotolerant and aggregates into clusters that are difficult to disperse.⁴²

The CDC has recommended infection prevention and control measures for C. auris.⁷ These include placing the patient in a single-patient room, using standard and contact precautions, adhering to hand hygiene, cleaning and disinfecting the patient care environment, and screening contacts of newly identified cases to identify colonization. Patients colonized with C. auris should adhere to these precautions for as long as colonization is present, which is defined as two or more negative colonization assessments at least 1 week apart in the absence of antifungal therapy.¹⁶

Currently, environmental disinfection is recommended with an Environmental Protection Agency-registered hospital-grade disinfectant effective against Clostridium difficile spores.⁷ Others have evaluated the use of chlorhexidine washing of patients and decontamination of environmental surfaces with hydrogen peroxide or bleach, which has yielded positive results.^40,43-49 However, a recent review concluded that no single disinfectant is accepted as effective for all surfaces and materials.⁴⁷

Summary

Pharmacists should be aware of the severity and challenges of infection with the emerging pathogen C. auris, as well as recommendations on its treatment and prevention. Patients with C. auris infection should be reported to appropriate public health authorities, and should receive infection prevention and control measures. Optimal therapy is not established because of its highly MDR resistance profile. The CDC has proposed treatment recommendations and tentative MIC breakpoints for C. auris. Recommended first-line therapy comprises an echinocandin, and therapy should be streamlined based on culture and sensitivity reports, which should be obtained for all cases. However, because of its recent emergence and limited study, pharmacists should be alert for changes in recommendations for management and prevention of C. auris infection as further data become available.

References

1.         American Academy of Pediatrics. Candidiasis. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018: 263-269.

2.         Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62:e1-50.

3.         Anonymous. Candida auris. Centers for Disease Control and Prevention website. https://www.cdc.gov/fungal/candida-auris/index.html. Updated July 23, 2018. Accessed August 1, 2018.

4.         Spivak ES, Hanson KE. Candida auris: an emerging fungal pathogen. J Clin Microbiol. 2018;56(2).

5.         Tsay S, Kallen A, Jackson BR, Chiller TM, Vallabhaneni S. Approach to the investigation and management of patients with Candida auris, an emerging multidrug-resistant yeast. Clin Infect Dis. 2018;66(2):306-311.

6.         Anonymous. Recommendations for treatment of Candida auris. Centers for Disease Control and Prevention website. https://www.cdc.gov/fungal/candida-auris/c-auris-treatment.html. Updated June 22, 2018. Accessed August 1, 2018.

7.         Anonymous. Recommendations for infection prevention and control for Candida auris. Centers for Disease Control and Prevention website. https://www.cdc.gov/fungal/candida-auris/c-auris-infection-control.html. Updated February 12, 2018. Accessed August 1, 2018.

8.         Satoh K, Makimura K, Hasumi Y, Nishiyama Y, Uchida K, Yamaguchi H. Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital. Microbiol Immunol. 2009;53(1):41-44.

9.         Lee WG, Shin JH, Uh Y, et al. First three reported cases of nosocomial fungemia caused by Candida auris. J Clin Microbiol. 2011;49(9):3139-3142.

10.       Schelenz S, Hagen F, Rhodes JL, et al. First hospital outbreak of the globally emerging Candida auris in a European hospital. Antimicrob Resist Infect Control. 2016;5:35.

11.       Anonymous. Clinical alert to U.S. Healthcare facilities – June 2016. Centers for Disease Control and Prevention website. https://www.cdc.gov/fungal/candida-auris/candida-auris-alert.html. Updated September 19, 2017. Accessed August 1, 2018.

12.       DynaMed Plus [database online]. Ipswich, MA: EBSCO; 2018. www.dynamed.com. Accessed August 1, 2018.

13.       Sears D, Schwartz BS. Candida auris: An emerging multidrug-resistant pathogen. Int J Infect Dis. 2017;63:95-98.

14.       Anonymous. Tracking Candida auris. Centers for Disease Control and Prevention website. https://www.cdc.gov/fungal/candida-auris/tracking-c-auris.html. Updated July 23, 2018. Accessed August 1, 2018.

15.       Osei Sekyere J. Candida auris: A systematic review and meta-analysis of current updates on an emerging multidrug-resistant pathogen. Microbiologyopen. 2018.

16.       Lee Y, Bao H, Viramgama S. A rare fungus on the rise: Candida auris. Am J Health Syst Pharm. 2018;75(14):1013-1017.

17.       Voelker R. New test identifies Candida auris. JAMA. 2018;319(21):2164.

18.       Mizusawa M, Miller H, Green R, et al. Can multidrug-resistant Candida auris be reliably identified in clinical microbiology laboratories? J Clin Microbiol. 2017;55(2):638-640.

19.       Kathuria S, Singh PK, Sharma C, et al. Multidrug-resistant Candida auris misidentified as Candida haemulonii: characterization by matrix-assisted laser desorption ionization-time of flight mass spectrometry and DNA sequencing and its antifungal susceptibility profile variability by Vitek 2, CLSI broth microdilution, and Etest method. J Clin Microbiol. 2015;53(6):1823-1830.

20.       Snayd M, Dias F, Ryan RW, Clout D, Banach DB. Misidentification of Candida auris by RapID Yeast Plus, a commercial, biochemical enzyme-based manual rapid identification system. J Clin Microbiol. 2018;56(5).

21.       Anonymous. Algorithm to identify Candida auris based on phenotypic laboratory method and initial species identification. Centers for Disease Control and Prevention website. https://www.cdc.gov/fungal/diseases/candidiasis/pdf/Testing-algorithm-by-Method-temp.pdf. Updated April 23, 2018. Accessed August 1, 2018.

22.       Anonymous. Recommendations for identification of Candida auris. Centers for Disease Control and Prevention website. https://www.cdc.gov/fungal/candida-auris/recommendations.html. Updated June 22, 2018. Accessed August 1, 2018.

23.       Anonymous. FDA authorizes new use of test, first to identify the emerging pathogen Candida auris. US Food and Drug Administration website. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm605336.htm. Published April 20, 2018. Accessed August 1, 2018.

24.       Sarma S, Upadhyay S. Current perspective on emergence, diagnosis and drug resistance in Candida auris. Infect Drug Resist. 2017;10:155-165.

25.       Chowdhary A, Prakash A, Sharma C, et al. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009-17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J Antimicrob Chemother. 2018;73(4):891-899.

26.       Kordalewska M, Lee A, Park S, et al. Understanding echinocandin resistance in the emerging pathogen Candida auris. Antimicrob Agents Chemother. 2018;62(6).

27.       Kumar D, Banerjee T, Pratap CB, Tilak R. Itraconazole-resistant Candida auris with phospholipase, proteinase and hemolysin activity from a case of vulvovaginitis. J Infect Dev Ctries. 2015;9(4):435-437.

28.       Sarma S, Kumar N, Sharma S, et al. Candidemia caused by amphotericin B and fluconazole resistant Candida auris. Indian J Med Microbiol. 2013;31(1):90-91.

29.       Lamoth F, Kontoyiannis DP. The Candida auris alert: Facts and perspectives. J Infect Dis. 2018;217(4):516-520.

30.       Schwartz IS, Hammond GW. First reported case of multidrug-resistant Candida auris in Canada. Can Commun Dis Rep. 2017;43(7-8):150-153.

31.       Anonymous. Ibrexafungerp (formerly SCY-078): An innovative antifungal. Scynexis website. https://www.scynexis.com/pipeline. Accessed August 2, 2018.

32.       Anonymous. Rezafungin. Cidara Therapeutics website. https://www.cidara.com/rezafungin/. Accessed August 2, 2018.

33.       Berkow EL, Angulo D, Lockhart SR. In vitro activity of a novel glucan synthase inhibitor, SCY-078, against clinical isolates of Candida auris. Antimicrob Agents Chemother. 2017;61(7).

34.       Berkow EL, Lockhart SR. Activity of CD101, a long-acting echinocandin, against clinical isolates of Candida auris. Diagn Microbiol Infect Dis. 2018;90(3):196-197.

35.       Hager CL, Larkin EL, Long L, Zohra Abidi F, Shaw KJ, Ghannoum MA. In vitro and in vivo evaluation of the antifungal activity of APX001A/APX001 against Candida auris. Antimicrob Agents Chemother. 2018;62(3).

36.       Hager CL, Larkin EL, Long LA, Ghannoum MA. Evaluation of the efficacy of rezafungin, a novel echinocandin, in the treatment of disseminated Candida auris infection using an immunocompromised mouse model. J Antimicrob Chemother. 2018;73(8):2085-2088.

37.       Larkin E, Hager C, Chandra J, et al. The emerging pathogen candida auris: Growth phenotype, virulence factors, activity of antifungals, and effect of SCY-078, a novel glucan synthesis inhibitor, on growth morphology and biofilm formation. Antimicrob Agents Chemother. 2017;61(5).

38.       Anonymous. SCYNEXIS, Inc. Receives orphan drug designation for scy-078 for the treatment of invasive aspergillus infections. Scynexis website. https://www.scynexis.com/news-media/press-releases/detail/82/scynexis-inc-receives-orphan-drug-designation-for-scy-078. Published August 24, 2016. Accessed August 2, 2018.

39.       Anonymous. Amplyx Pharmaceuticals receives fourth “Qualified Infectious Disease Product” (QIDP) designation from the FDA for APX001. Amplyx Pharmaceuticals website. https://amplyx.com/amplyx-pharmaceuticals-receives-fourth-qualified-infectious-disease-product-qidp-designation-from-the-fda-for-apx001/. Published March 12, 2018. Accessed August 2, 2018.

40.       Biswal M, Rudramurthy SM, Jain N, et al. Controlling a possible outbreak of Candida auris infection: lessons learnt from multiple interventions. J Hosp Infect. 2017;97(4):363-370.

41.       Piedrahita CT, Cadnum JL, Jencson AL, Shaikh AA, Ghannoum MA, Donskey CJ. Environmental surfaces in healthcare facilities are a potential source for transmission of Candida auris and other Candida species. Infect Control Hosp Epidemiol. 2017;38(9):1107-1109.

42.       Warris A. Candida auris, what do paediatricians need to know? Arch Dis Child. 2018.

43.       Abdolrasouli A, Armstrong-James D, Ryan L, Schelenz S. In vitro efficacy of disinfectants utilised for skin decolonisation and environmental decontamination during a hospital outbreak with Candida auris. Mycoses. 2017;60(11):758-763.

44.       Cadnum JL, Shaikh AA, Piedrahita CT, et al. Relative resistance of the emerging fungal pathogen Candida auris and other Candida species to killing by ultraviolet light. Infect Control Hosp Epidemiol. 2018;39(1):94-96.

45.       Cadnum JL, Shaikh AA, Piedrahita CT, et al. Effectiveness of disinfectants against Candida auris and other Candida species. Infect Control Hosp Epidemiol. 2017;38(10):1240-1243.

46.       Kean R, Sherry L, Townsend E, et al. Surface disinfection challenges for Candida auris: an in-vitro study. J Hosp Infect. 2018;98(4):433-436.

47.       Ku TSN, Walraven CJ, Lee SA. Candida auris: Disinfectants and implications for infection control. Front Microbiol. 2018;9:726.

48.       Moore G, Schelenz S, Borman AM, Johnson EM, Brown CS. Yeasticidal activity of chemical disinfectants and antiseptics against Candida auris. J Hosp Infect. 2017;97(4):371-375.

49.       Welsh RM, Bentz ML, Shams A, et al. Survival, persistence, and isolation of the emerging multidrug-resistant pathogenic yeast Candida auris on a plastic health care surface. J Clin Microbiol. 2017;55(10):2996-3005.

Prepared by:

Ryan Rodriguez, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

September 2018

The information presented is current as of July 31, 2018.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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What role does intravenous magnesium play in the management of migraines?

Background

Magnesium deficiency may play an important role in migraines, and numerous hypotheses exist regarding magnesium’s involvement in migraine pathophysiology.¹ Several studies showed that patients experiencing migraines are deficient in magnesium.^2-9 Magnesium regulates N-methyl-D-aspartate (NMDA) receptor by preventing entry of calcium into the cells.¹ At low levels of magnesium, NMDA receptor is activated causing calcium to enter cells, which in turn negatively affects neurons and cerebral vascular muscles. N-methyl-D-aspartate receptors can also affect cortical spreading depression (CSD), which contributes to aura associated with migraines. Low levels of magnesium cause changes in oxidative phosphorylation and neuronal polarization in the mitochondria, which in turn also influence CSD. Therefore, supplementation of magnesium may lead to the decrease of neurogenic inflammation and improvement in mitochondrial oxidative phosphorylation. Other theories link magnesium deficiency to the release of substance P, which acts on sensory fibers and produces headache pain.¹⁰ Therefore, a theory exists that supplementation of magnesium may be beneficial in patients with migraines.

Patients suffering from migraines can benefit from both, oral and intravenous, magnesium. Oral magnesium can play a role in chronic management of migraines.¹¹ One study showed that oral supplementation of magnesium resulted in the reduced frequency of migraine attacks.¹² On the other hand, intravenous (IV) magnesium is typically reserved for acute migraine attacks. This article explores the evidence, efficacy, and safety of IV magnesium in acute migraine attacks in adult patients.

Guidelines

In 2012, the American Academy of Neurology (AAN) released a guideline update on the pharmacologic management of episodic migraine prevention in adults.¹³ This guideline does not mention the use of magnesium, but the guideline’s update is currently in progress. At the same time, the AAN released another guideline update focusing on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and other complementary treatments for migraines in adults.¹⁴ The guideline concluded that oral magnesium is probably effective for migraine prevention, and therefore, this treatment should be considered for preventing migraines. The guideline did not address the use of IV magnesium. Unfortunately, the AAN retired this guideline in 2015.¹⁵

The American Headache Society (AHS) released several evidence assessments and guidelines from 2012 to 2016 that mention the use of magnesium in migraines.^16-18 Per the joint recommendation of AHS and AAN, oral magnesium (600 mg trimagnesium dicitrate daily) is an option for patients needing migraine prophylaxis. Other recommendations consist of administering IV magnesium in patients with migraine with aura in the urgent care or emergency department.^16,17 The AHS provides no recommendation for the use of magnesium in patients with migraine without aura.

Literature review

The literature regarding the use of IV magnesium in adult patients with acute migraine attacks remains limited. The trials exploring the use of IV magnesium for this indication have small sample sizes, differ in study designs and quality, and have varying comparators.^19,20 Making a clear conclusion regarding the benefits of IV magnesium is difficult due to conflicting results.

A meta-analysis, published in 2016, included 21 randomized controlled studies in English or Chinese to assess the effects of IV magnesium on acute migraines and oral magnesium supplements on migraine prophylaxis in adult patients.¹⁹ Compared to control groups, IV magnesium showed significant efficacy at relieving migraine at 15 to 45 min (pooled odds ratio (OR), 0.23; 95% confidence interval (CI), 0.09 to 0.58; p=0.002), at 120 min (pooled OR, 0.20; 95% CI, 0.10 to 0.40; p<0.001), and at 24 h (pooled OR, 0.25; 95% CI, 0.10 to 0.60; p=0.002). Control groups consisted of 0.9% saline, metoclopramide 10 to 20 mg, analgesics with antiemetics, and other agents depending on the study. The included studies had patients who had acute migraine attacks with and without aura. Oral magnesium showed significant results for the reduction in the frequency of migraines (pooled OR, 0.20; 95% CI, 0.05 to 0.89; p=0.04) and in the intensity of migraines (pooled OR, 0.27; 95% CI, 0.12 to 0.61; p=0.002).

On the other hand, a meta-analysis by Choi and Palmer of 5 randomized controlled trials in English showed statistically insignificant differences between IV magnesium and control groups for pain reduction at 30 min in adult patients with acute migraine attacks.²⁰ Control groups received placebo, IV metoclopramide 10 to 20 mg, or IV prochlorperazine 10 mg. The majority of included studies did not differentiate between migraines with aura versus without aura. Only the study by Bigal and colleagues performed analyses by the type of migraine and found a significant improvement with IV magnesium among patients with migraines with aura compared to placebo.²¹

Since the publication of the meta-analyses, Baratloo and colleagues published a prospective quasi-experimental study comparing IV magnesium sulfate to IV caffeine citrate for the management of acute migraine attack.²² The study took place in Iran and enrolled 70 adult patients with migraine attacks. Magnesium sulfate contributed to a significant decrease in visual analog scale pain scores at 1 h (p<0.001) and at 2 h (p<0.001) compared to caffeine citrate.

Administration considerations and safety

Most of the migraine studies utilized magnesium sulfate at doses of 1 to 2 g infused over 10 to 15 minutes.^21,23-27 One study allowed the administration of magnesium sulfate up to 3 doses every 15 minutes if needed for pain.²⁴

Several studies and a meta-analysis explored the safety of IV magnesium in patients with migraines.^{20,23,24,26,27} The meta-analysis by Choi and Palmer found that the percentage of patients in the magnesium group who experienced side effects or adverse events was 37% greater than the percentage of patients in the control group.²⁰ The meta-analysis did not expand on the type of side effects and adverse events that occurred. Individual studies revealed potential side effects with IV magnesium such as burning sensation in the face and neck, flushing, and slight drop in systolic blood pressure.^23,24,26,27 Flushing was the most common adverse event in these studies with some studies showing incidence in up to 85% of patients.

Conclusion

Numerous hypotheses exist regarding magnesium’s involvement in migraine pathophysiology. Current guidelines provide limited guidance on the use of IV magnesium, with the AHS providing recommendations on the use of IV magnesium primarily for migraines with aura in urgent care or emergency department settings.  The literature regarding the use of IV magnesium in adult patients with acute migraine attacks remains limited and shows conflicting results. A meta-analysis of randomized controlled trials in English and Chinese revealed significant benefits with IV magnesium for migraine relief with and without aura while another meta-analysis with randomized controlled trials in English did not show any significant benefits with IV magnesium.^19,20 Administration of IV magnesium sulfate during migraine attacks may cause side effects, mainly flushing. Providers must carefully consider available efficacy and safety data on IV magnesium sulfate in migraine attacks before making a decision regarding the use of this agent.

References

1.         Nattagh-Eshtivani E, Sani MA, Dahri M, et al. The role of nutrients in the pathogenesis and treatment of migraine headaches: review. Biomed Pharmacother. 2018;102:317-325.

2.         Gallai V, Sarchielli P, Coata G, Firenze C, Morucci P, Abbritti G. Serum and salivary magnesium levels in migraine. Results in a group of juvenile patients. Headache. 1992;32(3):132-135.

3.         Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Headache. 1991;31(5):298-301.

4.         Schoenen J, Sianard-Gainko J, Lenaerts M. Blood magnesium levels in migraine. Cephalalgia. 1991;11(2):97-99.

5.         Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulphate relieves migraine attacks in patients with low serum ionized magnesium levels: a pilot study. Clin Sci (Lond). 1995;89(6):633-636.

6.         Pfaffenrath V, Wessely P, Meyer C, et al. Magnesium in the prophylaxis of migraine–a double-blind placebo-controlled study. Cephalalgia. 1996;16(6):436-440.

7.         Trauninger A, Pfund Z, Koszegi T, Czopf J. Oral magnesium load test in patients with migraine. Headache. 2002;42(2):114-119.

8.         Aloisi P, Marrelli A, Porto C, Tozzi E, Cerone G. Visual evoked potentials and serum magnesium levels in juvenile migraine patients. Headache. 1997;37(6):383-385.

9.         Ramadan NM, Halvorson H, Vande-Linde A, Levine SR, Helpern JA, Welch KM. Low brain magnesium in migraine. Headache. 1989;29(9):590-593.

10.       Mauskop A, Varughese J. Why all migraine patients should be treated with magnesium. J Neural Transm (Vienna). 2012;119(5):575-579.

11.       Daniel O, Mauskop A. Nutraceuticals in acute and prophylactic treatment of migraine. Curr Treat Options Neurol. 2016;18(4):14.

12.       Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 1996;16(4):257-263.

13.       Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.

14.       Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1346-1353.

15.       Policy & guidelines: headache. American Academy of Neurology website. https://www.aan.com/Guidelines/home/ByTopic?topicId=16. Accessed August 15, 2018.

16.       Pringsheim T, Davenport WJ, Marmura MJ, Schwedt TJ, Silberstein S. How to apply the AHS evidence assessment of the acute treatment of migraine in adults to your patient with migraine. Headache. 2016;56(7):1194-1200.

17.       Orr SL, Friedman BW, Christie S, et al. Management of adults with acute migraine in the emergency department: the American Headache Society evidence assessment of parenteral pharmacotherapies. Headache. 2016;56(6):911-940.

18.       Loder E, Burch R, Rizzoli P. The 2012 AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines. Headache. 2012;52(6):930-945.

19.       Chiu HY, Yeh TH, Huang YC, Chen PY. Effects of intravenous and oral magnesium on reducing migraine: a meta-analysis of randomized controlled trials. Pain Physician. 2016;19(1):E97-112.

20.       Choi H, Parmar N. The use of intravenous magnesium sulphate for acute migraine: meta-analysis of randomized controlled trials. Eur J Emerg Med. 2014;21(1):2-9.

21.       Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia. 2002;22(5):345-353.

22.       Baratloo A, Mirbaha S, Delavar Kasmaei H, Payandemehr P, Elmaraezy A, Negida A. Intravenous caffeine citrate vs. magnesium sulfate for reducing pain in patients with acute migraine headache; a prospective quasi-experimental study. Korean J Pain. 2017;30(3):176-182.

23.       Demirkaya S, Vural O, Dora B, Topcuoglu MA. Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks. Headache. 2001;41(2):171-177.

24.       Corbo J, Esses D, Bijur PE, Iannaccone R, Gallagher EJ. Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache. Ann Emerg Med. 2001;38(6):621-627.

25.       Ginder S, Oatman B, Pollack M. A prospective study of i.v. magnesium and i.v. prochlorperazine in the treatment of headaches. J Emerg Med. 2000;18(3):311-315.

26.       Cete Y, Dora B, Ertan C, Ozdemir C, Oktay C. A randomized prospective placebo-controlled study of intravenous magnesium sulphate vs. metoclopramide in the management of acute migraine attacks in the emergency eepartment. Cephalalgia. 2005;25(3):199-204.

27.       Frank LR, Olson CM, Shuler KB, Gharib SF. Intravenous magnesium for acute benign headache in the emergency department: a randomized double-blind placebo-controlled trial. CJEM. 2004;6(5):327-332.

Prepared by:

Janna Afanasjeva, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

September 2018

The information presented is current as of August 17, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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What clinical data are available comparing meropenem 500 mg every 6 hours to meropenem 1000 mg every 8 hours?

Background

Meropenem is a carbapenem antibiotic that is approved by the Food and Drug Administration for treatment of complicated skin and skin structure infections and intra-abdominal infections in adults.¹ Meropenem is used off-label for many additional indications, including but not limited to bacteremia, febrile neutropenia, and pneumonia.² A traditional dosing regimen of meropenem is 1000 mg administered over 30 minutes every 8 hours.³ However, one alternative dosing strategy that has been evaluated is meropenem 500 mg every 6 hours.

The bactericidal activity of meropenem is correlated with the time the plasma concentration of drug is above the minimum inhibitory concentration of the pathogen (%T/MIC).^3,4 Because the bactericidal activity of meropenem is time-dependent, it is theorized that administering meropenem at a lower dosage of 500 mg over more frequent intervals of every 6 hours may have similar efficacy to the traditional dosing.³ Pharmacodynamic analysis has demonstrated similar pharmacodynamic target attainment rates between the two dosing strategies (1000 mg every 8 hours vs 500 mg every 6 hours).^3,4 Because the alternative dosing strategy uses a lower total daily dose, changing to the alternative regimen may provide cost savings as well. Therefore, the purpose of this review is to evaluate data assessing clinical outcomes in studies comparing meropenem 1000 mg every 8 hours (traditional dosing) to 500 mg every 6 hours (alternative dosing).

Evidence

A literature search of MEDLINE performed in June 2018 identified 4 retrospective studies that included clinical outcomes and compared meropenem 500 mg every 6 hours to 1000 mg every 8 hours.^5-8 These articles are summarized in the Table. Studies that evaluated only pharmacodynamic or pharmacokinetic parameters were not included. Additionally, a study that compared meropenem 1000 mg every 8 hours administered via extended infusion (over 3 hours) to meropenem 500 mg every 6 hours over 30 minutes was excluded because the extended infusion is not the traditional dosing modality.⁹

All studies were retrospective, single-center analyses with limited numbers of patients.^5-8 Generally, the studies did not find significant differences in clinical outcomes including clinical success rate,^5,7,8 in-hospital mortality,^6,7 30-day mortality,^5,6 or time to defervescence^5,6,8 between groups. However, one study by Patel and colleagues found median time to resolution of infection was lower with alternative dosing (1.5 days) compared to traditional dosing (3 days) (p<0.0001).⁷ Data on the safety of the alternative regimen are limited. One study found similar adverse events between the two treatment regimens.⁸

The available studies generally reported savings to the hospitals based on drug costs when the alternative regimen was used; however, costs were not significantly different in the study by Kotapati and colleagues when total hospital costs for the meropenem-related length of stay were evaluated.^5,7,8 The US analyses were based on older prices, so may not be reflective of current costs.^7,8 Notably, the study by Chow et al was conducted in Canada so cost data may not be generalizable to the United States.⁵

Table. Comparative studies of traditional and alternative dosing of meropenem.^5-8

Conclusion

Overall, data to support the alternative dosing of meropenem is limited and based on retrospective, single-center analyses with small study populations which may not be adequately powered to detect differences between groups. However, it is unlikely that a prospective, randomized, non-inferiority study will be conducted. Additionally, there are limited data on safety of the alternative regimen. Current available evidence generally does not demonstrate significant differences in clinical outcomes between alternative and traditional meropenem dosing.  There is suggestion of cost savings with use of meropenem 500 mg every 6 hours.

References

1.         Merrem [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018.

2.         LexiComp Online. 2018. http://online.lexi.com/lco/action/home. Accessed August 21, 2018.

3.         Wilby KJ, Nasr ZG, Elazzazy S, Lau TT, Hamad A. A review of clinical outcomes associated with two meropenem dosing strategies. Drugs R D. 2017;17(1):73-78.

4.         Perrott J, Mabasa VH, Ensom MH. Comparing outcomes of meropenem administration strategies based on pharmacokinetic and pharmacodynamic principles: a qualitative systematic review. Ann Pharmacother. 2010;44(3):557-564.

5.         Chow I, Mabasa V, Chan C. Meropenem assessment before and after implementation of a small-dose, short-interval standard dosing regimen. Can J Hosp Pharm. 2018;71(1):14-21.

6.         Arnold HM, McKinnon PS, Augustin KM, et al. Assessment of an alternative meropenem dosing strategy compared with imipenem-cilastatin or traditional meropenem dosing after cefepime failure or intolerance in adults with neutropenic fever. Pharmacotherapy. 2009;29(8):914-923.

7.         Patel GW, Duquaine SM, McKinnon PS. Clinical outcomes and cost minimization with an alternative dosing regimen for meropenem in a community hospital. Pharmacotherapy. 2007;27(12):1637-1643.

8.         Kotapati S, Nicolau DP, Nightingale CH, Kuti JL. Clinical and economic benefits of a meropenem dosage strategy based on pharmacodynamic concepts. Am J Health Syst Pharm. 2004;61(12):1264-1270.

9.         Ahmed N, Jen SP, Altshuler D, Papadopoulos J, Pham VP, Dubrovskaya Y. Evaluation of meropenem extended versus intermittent infusion dosing protocol in critically ill patients [published online ahead of print January 1, 2018]. J Intensive Care Med. doi: 10.1177/0885066618784264.

Prepared by:

Patricia Hartke, PharmD

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

September 2018

The information presented is current as of June 15, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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