Optimizing Antibiotic Use in 2015 Jamie McCarrell, Pharm.D., BCPS, CGP Assistant Professor, TTUHSC SOP/SOM

Objectives Review new antibiotics approved for use by the FDA for various bacterial infections. Identify current trends in resistance for common multi-drug resistant bacteria. Develop strategies for appropriately dosing antibiotics in patients with varying degrees of renal dysfunction. Outline major points from several landmark guidelines for acute bacterial syndromes. Given a patient case, optimize antibiotic pharmacotherapy to adequately treat the bacterial infection while minimizing adverse effects.

2014-2015 New antibiotics

Zerbaxa® Ceftolozane/tazobactam 5th generation cephalosporin Indications: Intra-abdominal infections, complicated UTIs Key features: ~$100/gram (dosed 1.5 gm Q8h for 4-14 days) Covers Pseudomonas aeruginosa Must use with Flagyl for intra-abdominal infections Crosses placenta, but Category B

Orbactiv® Oritavancin Lipoglycopeptide (inhibits cross-linking of cell wall membrane) Indications: ABSSSI due to Gram (+) including MRSA (but not VRE) Key Features: Single dose therapy (t1/2 = 245 hours!) Cost = $3480 for single dose

Dalvance® Dalbavancin Lipoglycopeptide (inhibits cross-linking of cell wall membrane) Indications: ABSSSI due to Gram (+) infections including MRSA Key Features: One dose with one follow-up dose 7 days later Cost: Initial dose = $3576, FU dose = $1788

Sivextro® Tedizolid Oxazolidinone Indications: ABSSI due to Gram (+) infections including MRSA Key features: Price = $2124 (oral), $2820 (IV) for 6 days May be useful in linezolid-resistant infections

Kerydin® Tavaborole Oxaborole antifungal (inhibits tRNA synthesis) Indications: onychomycosis Key Features Duration of therapy: 48 weeks (daily) Cost/bottle = $589, which lasts 3 weeks Cost/treatment = $9,424 Chance of cure = 6.5 – 9.1%

Jublia® Efinaconazole Azole antifungal, inhibits fungal cell membrane synthesis Indications: Onychomycosis Key features: Duration of therapy: 48 weeks (daily) Cost/bottle = $539, which lasts 3 weeks Cost/treatment = $8,624 Chance of cure = 15 – 17%

Xtoro® Finafloxacin otic solution Fluoroquinolone Indications: Swimmer’s ear Key features Covers Staph aureus and Pseudomonas aeruginosa Approved 12/2014 Cost info not yet available

Trends in resistance

Vancomycin MIC “Creep” occurring nationally Occurs in MSSA and MRSA Higher MICs associated with higher rates of Tx failure and mortality VRSA – multiple cases on multiple continents

The “D-Test” “Erm” gene Induced by ERY Causes clinda resistance The “erm” gene…Can initially show resistance to ERY but susceptible to clinda…ERY will induce the erm gene and cause clindamycin resistance. Clinically relevant why? http://microblog.me.uk/wp-content/uploads/TheDtest.jpg

Carbapenemases Class A – Klebsiella pneumoniae carbapenemase (KPC) Class B – Metallo-β-Lactamases (MBL) Class D – OXA – 48 type

Systemic Gram Negative HOUSEWIDE # of isolates UNASYN AMIKACIN AMPICILLIN AUGMENTIN AZACTAM ROCEPHIN FORTAZ CLAFORAN ANCEF ZINACEF GENTAMICIN PRIMAXIN LEVAQUIN ZOSYN BACTRIM TETRACYCLINE TIMENTIN TOBRAMYCIN Citrobacter freundii 5 40 100 20 60 80 67 Enterobacter aerogenes 7 43 86 29 57 71 14 Enterobacter cloacae 19 37 89 11 47 74 68 79 26 84 95 Escherichia coli 102 44 99 35 81 76 83 94 70 62 90 Klebsiella oxytoca 8 75 50 88 Klebsiella pneumoniae 27 93 96 Pseudomonas aeruginosa 38   53 24 61 Proteus mirabilis 23 78 87 65 Stenotrophomonas maltophilia 25 Serratia marcesens Shigella sonnei Salmonella 1 The shaded areas represent a 10% or greater decrease in sensitivity.

UTI- Adult Women Uncomplicated Cystitis Nitrofurantoin 100 mg PO BID x 5 days Bactrim DS, 1 tab PO BID X 3 days FQN 3 day regimens Side effects, resistance issues  reserve Beta-lactams 3-7 day regimens, only when recommended agents can’t be used Amoxicillin or ampicillin NOT recommended for empiric therapy

UTI – Geriatric Women Nitrofurantoin issues Bactrim issues Beers criteria CrCl cutoff (later slide) Bactrim issues New study…sudden death risk? Hyperkalemia Risk of INR fluctuations

UTI – Geriatric Women Levofloxacin issues Renal dose adjustments (later slide) QTc prolongation Mental status changes Tendon rupture Drug interactions Difficult to make a good choice…must consider all aspects of the patient before deciding on empiric therapy in the elderly!

Renal adjustment of antibiotics More Isn’t Always Better Renal adjustment of antibiotics

CrCl vs MDRD Levaquin® Desired Dose CrCl > 50 ml/min 20 – 49 ml/min 750 mg daily 750 mg Q48 hrs 750 mg x1, then 500 mg Q48 hrs 500 mg daily 500 mg x1, then 250 mg Q24 hrs 500 mg x1, then 250 mg Q48 hrs 250 mg daily 250 mg Q48 hrs CrCl vs MDRD

Vancomycin Loading dose of 25 – 30 mg/kg Maintenance: 15 – 20 mg/kg/dose every 8-12 hours (adjusted to desired trough) Note: MIC = 1 mcg/ml requires trough of 15 Renal dysfunction: CrCl > 50: No adjustment CrCl 20 – 49: increase interval to Q24h CrCl < 20: Pharmacokinetic modeling Oral administration: No adjustments

Nitrofurantoin CrCl > 60 ml/min is required to get adequate concentration Debatable… Pulmonary toxicity if not cleared Free radical formation = tissue damage Allergic and eosinophilic response as well

Other Antibiotics Safe to assume adjustments are needed… Nearly all antibiotics require some adjustment. Can check drug references or package labeling…or call the pharmacist! Benefits of proper dosing: Minimize adverse effects and kidney injury Minimize patient costs and QOL

Pneumonia Guidelines - Review IDSA – CAP Previously healthy, no Abx for 3 months Macrolide Alternative: Doxycycline Comorbidities OR inpatient Respiratory FQN: Levo, Moxi Beta-lactam + Macrolide (R & Z) ICU Beta-lactam + Resp FQN Alternative: Beta-lactam + Macrolide

Group work Patient case