HYMR1

Wednesday, May 25, 2016

Trick of the Trade: Simplify Treatment of the SSTI

In 2010, skin and soft tissue infections (SSTIs) accounted for approximately 4.2 million emergency department visits (1). With such a bread-and-butter emergency medicine encounter, one might not give a second thought as to whether the standard dosing is less than ideal. However, the nuance of appropriate pharmacokinetic dosing that drug references omit may be the more ideal approach. The most appropriate dosing regimen, based on pharmacokinetic parameters, may not be highlighted by tertiary drug resources (2).With a condition seen every day, we should be nailing the treatment. If we see it every day, we should be excellent at treating it, right?

Let’s start with the organisms likely to cause these infections. Generally, gram (+) streptococcal and staphylococcal species are our biggest offenders. For streptococcus, we can utilize first-generation cephalosporins or penicillins. Between 20-50% of SSTIs are secondary to community-acquired methicillin-resistant staphylococcus aureus (MRSA) (3). The Infectious Diseases Society of America guidelines offer insight for purulent and nonpurulent SSTIs, but does not specifically address the scenario of a purulent infection with cellulitis (4). For these patients we often prescribe two antibiotics, adding MRSA coverage with trimethoprim-sulfamethoxazole (Bactrim, TMP/SMX) or doxycycline based on local susceptibilities. In addition, recent literature comparing TMP/SMX to placebo for uncomplicated skin abscesses after drainage found significantly higher cure rates for those who received TMP/SMX (5). If there is concern for streptococcus, TMP/SMX has poor streptococcal coverage and an additional antimicrobial agent should be added, which is often cephalexin.

When prescribing cephalexin, we need to dose it appropriately. So, how do you dose cephalexin in an adult with normal renal function? If you went to a tertiary reference you might see something like the screenshots below.

UpToDate© 

Micromedex©
All of these doses seem reasonable. To maximize adherence you might reach for the 500 mg every 12 hours, because who wants to take an antibiotic four times a day? Especially if also sending the patient home with TMP/SMX, the pill burden grows quickly to 6-8 daily depending on your TMP/SMX dose (see TMP/SMX dosing strategy on ALiEM).

Let’s review the pharmacokinetics and pharmacodynamics of cephalexin. As with all cephalosporins, cephalexin is a time-dependent antibiotic. In other words, this antibiotic needs to be dosed multiple times per day to ensure that the concentration does not fall below the minimum inhibitory concentration, or you risk resistance and insufficient antimicrobial killing (6).

“UpToDate said every 12 hours was okay so…”

To choose the appropriate frequency, we must look to the half-life. The half-life of cephalexin is between 0.5 and 1.5 hours for patients with normal renal function (6,7). In about 5 half-lives, or roughly 5 hours, this drug is almost entirely removed from the body. Therefore, every 12 hours dosing should never be an option for patients with normal renal function. Prescription costs can often be an issue and sending a patient out with two antibiotics may be less than ideal. This is often the burden patients face when providers prescribe cephalexin and TMP/SMX for SSTI outpatient therapy.

Trick of the Trade 

For uncomplicated, adult cellulitis, administer a one-time intramuscular injection of Bicillin L-A (benzathine penicillin [PCN] G) at a dose of 1.2 million units in lieu of oral cephalexin every 6 hours to provide streptococcal coverage. Benzathine PCN G has an exceptionally long duration of action, more than sufficient to cover 7-10 days of treatment (8).


Anyone who has received an IM injection of benzathine PCN G will tell you the major drawback is pain, which can last several days. For some providers, this has been a deterrent for prescribing the drug unless it is absolutely indicated. Shared decision-making with the patient may be useful when discussing the advantages and disadvantages of an IM injection of benzathine PCN G.

Can we give this to every patient with some form of cellulitis? Of course not. Allergies must be thoroughly investigated and past medical history reviewed. Patients with diabetes, psoriasis, obesity (BMI > 32), elderly age, or lower extremity cellulitis with impaired venous drainage (varicose veins, deep-venous thrombosis, stasis dermatitis) are at risk for treatment failure with benzathine PCN G (9,10).

The IDSA guidelines recommend IM benzathine PCN G as an option for recurrent cellulitis prophylaxis and oral therapy for treatment of a mild cellulitis (3,8). One may consider use of benzathine PCN G for these mild cellulitis cases as a means to ensure 100% medication compliance.

For a patient that would have been prescribed cephalexin and TMP/SMX for their SSTI, consider simplifying their regimen with a one-time benzathine PCN G IM injection and a single prescription for TMP/SMX.

Note: Bicillin L-A is currently on backorder due to manufacturing delays and expected to resolve by July 2016 as of 5/11/2016 (FDA Drug Shortages).

Grace Benanti, PharmD (@gracebenanti)
Pharmacy Practice Resident (PGY1)
Banner - University Medical Center Phoenix
Phoenix, Arizona

Mark Culver, PharmD, BCPS (@EMdruggist)
Emergency Medicine Pharmacist
Banner - University Medical Center Phoenix
Phoenix, Arizona

Peer reviewed by: Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

References:

1. Prusakowski MK, Kuehl DR. Trends in emergency department management of skin abscesses. Am J Infect Control. 2015;43(4):336-40.
2. Randhawa AS, Babalola O, Henney Z, et al. A Collaborative Assessment Among 11 Pharmaceutical Companies of Misinformation in Commonly Used Online Drug Information Compendia. Ann Pharmacother. 2016;50(5):352-9.
3.Wackett A, Nazdryn A, Spitzer E, Singer AJ. MRSA rates and antibiotic susceptibilities from skin and soft tissue cultures in a suburban ED. J Emerg Med. 2012;43(4):754-7.
4. Stevens DL, Bisno AL, Chambers HF, et al: Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of america. Clin Infect Dis 2014; 59(2):e10-e52.
5. Talan DA, Mower WR, Krishnadasan A, et al. Trimethoprim-Sulfamethoxazole versus placebo for uncomplicated skin abscess. N Engl J Med. 2016;374(9):823-32.
6. Keflex (cephalexin) capsules [prescribing information]. Florham Park, NJ: Shionogi; October 2015.
7. Bergan T. Pharmacokinetic properties of cephalosporins. Drugs 1987; 34 (Suppl 2):89-104.
8. Bicillin L-A suspension for IM injection (penicillin G benzathine injectable suspension) [prescribing information]. Bristol, TN: King Pharmaceuticals; 2006.
9. Wang JH, Liu YC, Cheng DL, et al. Role of benzathine penicillin G in prophylaxis for recurrent streptococcal cellulitis of the lower legs. Clin Infect Dis. 1997;25(3):685-9.
10. Karppelin M, Siljander T, Huhtala H, et al. Recurrent cellulitis with benzathine penicillin prophylaxis is associated with diabetes and psoriasis. Eur J Clin Microbiol Infect Dis. 2013;32(3):369-72.

Wednesday, May 4, 2016

Euglycemic DKA from SGLT2 Inhibitors: Don't Worry, I Can't Pronounce Them Either

Diabetic ketoacidosis in patients with presenting serum blood glucose less than 200 is not common. Particularly when practicing in the Bible/Diabetes belt of the United States. This euglycemic DKA (euDKA) is more often associated in patients with type 1 diabetes in conjunction with starvation and acute illness.[1] It's difficult to determine an incidence of euglycemic serum glucose among all DKA cases in the literature given the migration of the serum glucose cutoff from 300 or less to 200 or less. The best estimation based on an analysis of case reports suggests an incidence anywhere from 0.8% to 7.5%.[1] However, the newest class of unpronounceable medications, the sodium-glucose co-transporter 2 inhibitors (SGLT2inh) (canagliflozin, dapagliflozin, empagliflozin) are making their presence known by inducing this once rare form of DKA.[2-3]

SGLT2inhs are a class of oral hypoglycemic drugs indicated only for type 2 diabetes. Their novel mechanism of action prevents glucose reabsorption from the proximal renal tubules resulting in increased glucosuria and decreasing plasma glucose. The resulting effects include lower serum glucose levels, lower HBA1C, and even weight loss. But that's not all. The increased glucose concentration in the bladder is a terrific incubation environment for fungi and bacteria. So much so that the FDA has slapped a post-marketing warning on the drug class for the increased risk of UTI and urosepsis.

In other patients, euglycemic DKA may occur. This too has led to the FDA issuing a similar warning of this possible life threat.  The proposed mechanism suggests that SGLT2inhs while lowering serum glucose, also reduces insulin secretion from pancreatic beta cells in a negative feedback fashion. The lower serum insulin coupled with lower serum glucose consequently shifts energy metabolism to antilipolytic activity and thus free fatty acid oxidation and ketosis. In addition, its postulated that this SGLT2inh induced insulin deficiency may promote fatty acid oxidation due to decreased production of malonyl-CoA which would normally inhibit the transport of FFA into mitochondira via carnitine palmitoyltransferase-I. Increased glucagon secretion is the cherry on top. (See the illustration below from reference 2)



Explaining why, of the estimated 40,000 patients taking these medications, only a small proportion ever manifest euDKA becomes pharma-nerdy. One possible mechanism involves alterations in the metabolism of these drugs through genetic mutations. The normal metabolic pathway for the SGLTinhs involves UGT1A9 producing inactive metabolites. However, known polymorphisms of UGT1A9 (potentially allele *3 and *22) may alter the expression of genes coding UGT1A9 and alter its metabolic activity.[4-7] The end result being active drug accumulation leading to profound glucosuria, insulin secretion depression and subsequently FFA oxidation. Although the clinical implications of this polymorphism aren't known and pharmacogenomic research rarely leads to cost effective screening methods to prevent given adverse events.

In terms of management, these patients should be treated as any other DKA patient would. That is, if the entire treating team understands the treatment goals of DKA: correction of acidosis... Not just normoglycemia. Failure to start insulin with dextrose will cause the outlined mechanism to persist and potential worsening of the metabolic picture. That may mean starting an insulin drip at 0.1 unit/kg/hr with D10W on a patient with a glucose of 130 mg/dL. These patients should be responsive to insulin/dextrose since the pathophysiology does not involve exacerbated insulin resistance. However, there is no evidence suggesting lower insulin doses should be substituted for conventional dosing for DKA. When considering the patient's home diabetes regimen, they should no longer receive any of the SGLT2inh since the manifestation of euDKA should be considered a class effect.

Take home points:
  • SGLT2 inhibitors, although unpronounceable, can cause serious badness in the form of nasty UTI and euDKA.
  • Don't let normal finger-stick glucose deter from further workup if clinical signs and symptoms fit DKA.
  • UTG 1A9 polymorphisms may be the culprit.
  • It's still DKA- you know how to treat it. Just make sure everyone else is on the same page.

References:

1) Joseph F, et al.Starvation-induced True Diabetic Euglycemic Ketoacidosis in Severe Depression. J Gen Intern Med. 2009 Jan; 24(1): 129–131
2) Ogawa W, et al. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. Journal of Diabetes Investigation, 2016:7(2)135-138
3) Rosenstock J, et al. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care. 2015 Sep;38(9):1638-42
4) Kasichayanula S, et al. Clinical Pharmacokinetics and Pharmacodynamics of Dapagliflozin, a Selective Inhibitor of Sodium-Glucose Co-transporter Type 2. Clinical Pharmacokinetics January 2014;53(1): 17-27
5) Jiao Z, et al. Population pharmacokinetic modelling for enterohepatic circulation of mycophenolic acid in healthy Chinese and the influence of polymorphisms in UGT1A9. Br J Clin Pharmacol. 2008 Jun;65(6):893-907
6) Yamanaka H, et al. A novel polymorphism in the promoter region of human UGT1A9 gene (UGT1A9*22) and its effects on the transcriptional activity. Pharmacogenetics. 2004 May;14(5):329-32
7) Pattanawongsa A, et al. Inhibition of Human UDP-Glucuronosyltransferase Enzymes by Canagliflozin and Dapagliflozin: Implications for Drug-Drug Interactions. Drug Metab Dispos. 2015 Oct;43(10):1468-76

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