2/15/2017

Antibiotics and

Christina Pornprasert, PharmD Population Health Clinical Pharmacist Hartford Healthcare Integrated Care Partners

Assistant Clinical Professor University of Connecticut School of Pharmacy

February 16, 2017

Objectives

• Review considerations for initiating antibiotic therapy in diabetic foot infections

• Identify antibiotics that increase risk for blood sugar swings

• Identify antidiabetic medications that increase risk for infections

• Recognize drug interactions between antibiotics and antidiabetic medications

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Link between High Blood and Infection Risk

• Increased susceptibility to infections

• elevates dicarbonyls (methylglyoxal and glyoxal)  inhibition of beta-defensins

• More adversely affected after acquiring infections

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Infections in Patients with Diabetes

• Skin and Soft Tissue Infections • Osteomyelitis • Urinary Tract Infections • Ear, Nose, Throat

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Diabetic Foot Infections

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Diabetic Foot Infections: Assess for infection

• ≥ 2 clinical signs of inflammation or purulence

• Severity – Mild (superficial, limited in size/depth) – Moderate (deeper or more extensive) • Abscess, osteomyelitis, septic arthritis, fasciitis – Severe (systemic signs or metabolic perturbations)

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Diabetic Foot Infections: Risk Factors

• Wound with positive probe-to-bone (PTB) test • Ulceration > 30 days • Hx of recurrent foot ulcers • Traumatic foot wound • Peripheral vascular disease in affected limb • Previous lower extremity amputation • Loss of protective sensation • Renal insufficiency • Hx of walking barefoot

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Diabetic Foot Infections: Assess for treatment

• Clinically uninfected wounds: do not collect culture • Infected wounds: culture prior to starting antibiotic therapy

**Avoid prescribing antibiotics for clinically uninfected wounds**

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Diabetic Foot Infections: Questions to Consider

• Is there clinical evidence of infection?

• For clinically infected wounds: – Is there high risk of MRSA? – Has patient received antibiotics (abx) in the past? – Are there risk factors for Pseudomonas infection? – What is the infection severity status?

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Diabetic Foot Infections: Antibiotic Therapy

Mild to moderate infection with Target gram-positive cocci, no recent abx treatment especially Staphylococci

Severe infection Broad-spectrum empiric therapy

Risk factors for Pseudomonas Empiric therapy directed at aeruginosa Pseudomonas aeruginosa

Prior hx of MRSA infection, local prevalence of MRSA Empiric therapy directed at MRSA colonization/infection high, or clinically severe infection

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Diabetic Foot Infections: Mild

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Diabetic Foot Infections: Moderate or Severe

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Diabetic Foot Infections: Moderate or Severe

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Diabetic Foot Infections: Moderate or Severe

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Diabetic Foot Infections: Duration of Therapy

• Mild infection: 1-2 weeks • Moderate/severe infection: 2-3 weeks

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Antibiotics and Blood Sugar Swings

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• Classes – Fluoroquinolones • moxifloxacin, levofloxacin, ciprofloxacin

– Second-generation cephalosporins • cefuroxime, cefaclor, cefprozil

– Macrolides • clarithromycin, azithromycin

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• ED visits or hospitalizations for dysglycemia within 30 days of starting antibiotic therapy

• Dysglycemia – : ICD-9 codes with IV dextrose Rx’s – HYPERglycemia: ICD-9 codes with Rx’s

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Absolute Risk of Hypoglycemia and Hyperglycemia per 1,000 people

HYPOglycemia HYPERglycemia Fluoroquinolones - Moxifloxacin 10.0 6.9 -Levofloxacin 9.3 3.9 - Ciprofloxacin 7.9 4.0

Macrolides 3.7 1.6

Cephalosporins 3.2 2.1

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• Highest risk of hypoglycemia: – Moxifloxacin > levofloxacin > ciprofloxacin

• Consider the higher risk when treating diabetic patients with fluoroquinolones, especially moxifloxacin

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Antidiabetic Medications and Risk of Infection Dipeptidyl peptidase-4 (DPP4) inhibitors Glucagon-like peptide-1 (GLP1) receptor agonists Sodium-glucose cotransporter-2 (SGLT2) inhibitors

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SGLT2 inhibitors - canagliflozin (Invokana) - dapagliflozin (Farxiga) - empagliflozin (Jardiance)

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SGLT2 inhibitors: Mechanism of Action

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SGLT2 inhibitors

• Genitourinary Infections – Urinary tract infections – Genital infections (vaginitis, vulvovaginal candidiasis, balanitis)

• Contributory Factors – Bacteriuria associated with glycosuria – Increased adherence of Escherichia coli to uroepithelial cells – Increased virulence of Candida albicans in suboptimal glycemic control – Immune dysfunction associated with hyperglycemia

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SGLT2 inhibitors: Genital Infections (mycotic balanitis and vulvovaginitis)

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SGLT2 inhibitors

• Evaluate for risk factors for genitourinary infections – Hx of genitourinary infections – Younger patients – Female > Male – Uncircumcised males

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DPP4 inhibitors GLP1 agonists - sitagliptin (Januvia) - exenatide (Byetta/Bydureon) - saxagliptin (Onglyza) - liraglutide (Victoza) - linagliptin (Tradjenta) - dulaglutide (Trulicity) - alogliptin (Takeda) - albiglutide (Tanzeum) - lixisenatide (Adlyxin)

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DPP4 inhibitors and GLP1 agonists

• Upper respiratory tract infections – Nasopharyngitis – Acute bronchitis – Pharyngitis – Sinusitis – Rhinitis

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Drug Interactions: Antibiotics and Antidiabetic Medications

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Principles of Drug Interactions

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Drug Interactions in Liver

↑ glipizide glipizide

Bactrim

glipizide rifampin ↓ glipizide

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Drug Interactions with (glipizide, glimepiride, glyburide)

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Drug Interactions with

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Drug Interactions with Thiazolidinediones (pioglitazone, rosiglitazone)

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Drug Interactions with DPP4 inhibitors

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Drug Interactions: Summary

• Anti-infection interactions that may warrant tight BG monitoring and dose adjustment of sulfonylureas (2C9 and Pgp substrate), TZDs (2C8 substrate), and saxagliptin (3A4 and Pgp substrate):

– CYP/Pgp inhibitors • Azole antifungals • Clarithromycin • Sulfamethoxazole/trimethoprim (Bactrim) • Tazanavir/ritonavir

– CYP/Pgp inducers • Rifampin

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Drug Interactions: Summary

• Polypharmacy is common in patients with diabetes

• Increasing age  ↓ liver and renal capacity – ↓ ability to metabolize and eliminate drugs

• Increased fall risk d/t hypoglycemia

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Resources

• Chaplin S. SGLT2 inhibitors and risk of genitourinary infections. Prescriber. December 2016. • Chou H, Wang J, Chang C, et al. Risk of Severe Dysglycemia Among Diabetic Patients Receiving Levofloxacin, Ciprofloxacin, or Moxifloxacin in Taiwain. Clinical Infectious Diseases. 2013;57(7):971-980. • Chao E. SGLT-2 Inhibitors: A New Mechanism for Glycemic Control. Clinical Diabetes. Volume 32, November 1, 2014. • Doyle M, Egan J. Mechanisms of Action of GLP-1 in the Pancreas. Pharmacol Ther. 2007 Mar; 113(3):546-593. • FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. 4 December 2015. • Khardori, R. Infection in Patients with Diabetes Mellitus. Drug and Diseases: Endocrinology. Medscape. Accessed December 2016.

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Resources

• Lipsky B, Berendt A, Cornia P, et al. 2012 Infectious Disease Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections. Clinically Infectious Diseases. 2012;54(12):132-173. • Standards of Medical Care in Diabetes– 2017. American Diabetes Association. January 2017. Volume 40, Supplement 1. • Study Examines Risk of Severe Blood Sugar Swings Among Diabetics Taking Fluoroquinolones. Clinical Infectious Diseases. 15 August 2013. • Triplitt C. Pharmacy Update: Drug Interactions of Medications Commonly Used in Diabetes. Diabetes Spectrum. Volume 19, Number 4, 2006. • Trujilo J, Nuffer W, Ellis S. GLP-1 receptor agonists: a review of head-to-head clinical studies. Therapeutic Advances in Endocrinology and Metabolism. 2015, Vol. 6(1) 19-28. • Willemen M, Mantel-Teeuwisse A, Straus S, et al. Use of Dipeptidyl Peptidase-4 Inhibitors and the Reporting of Infections: A Disproportionality Analysis in the World Health Organization VigiBase. Diabetes Care 2011 Feb; 34(2)369-374.

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