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Home , Cefepime, Daptomycin, Nafcillin

MICU and Associated Drug Interactions

Resistant

► MICU patient are at risk for resistant organisms: § Recent hospitalizations § From a skilled nursing facility § Immunocompromised patients ►Transplant population ►Chronic steroid use Organisms of Concern

► Gram Negative organisms § § Acinetobacter § Klebsiella pneumoniae ► ESBL § E.Coli ► ESBL ► Staph Aureus § MRSA ► faecalis & faecium § VRE Management Program (AMP)

► Patient safety initiative to address: § The related to C. difficile § Increasing § Increasing antimicrobial cost

Commonly Used Restricted Antibiotics

► Must call AMP to get an approval code (Full list on page 12 of Guide to Antimicrobial Chemotherapy) § Commonly used agents ► Ciprofloxacin ► Moxifloxacin ► ► ► ► ► ► ► ► ► Oral —unless you fill out a C.diff order set Not Restricted in the ICU

► Vancomycin ► Zosyn (piperacilin/) ► ► Aminoglycosides § Gentamicin § Tobramycin Pharmacodynamics

► Concentration dependant killing ► Goal: maximize the concentration § AUC/MIC ratio and Peak/MIC are predictors of efficacy § Antibiotics kill with increasing antibiotic concentrations at a greater rate and extent § Aminoglycosides ►Fluoroquinolones ►Metronidazole Pharmacodynamics

► Time dependent killing ► Goal: Maximize duration of exposure § T > MIC correlates best with efficacy ►Antibiotics kill bacteria at the same rate and extent once an appropriate a threshold concentration is achieved § Increasing concentration does not augment the antibacterial activity ►Vancomycin, clindamycin, macrolides and ß-lactams Pharmacodynamics of Time Dependant Killers: (Beta-Lactams and Macrolides)

Craig et al, Ped Infect Dis 15: 255, 1996 Concentration vs. Time dependant Killing Post Antibiotic Effect

► The continued suppression of antibacterial growth § After the administration of antibiotic has ceased § Serum concentrations have fallen below the minimum inhibitory concentration Post Antibiotic Effect

3 hour PAE

Antibiotic is stopped Specific Antibiotics Vancomycin Indications (pg . 17 Abx book) ► Treatment of: § Serious infections due to beta-lactam resistant gram positive micro- organisms § Gram positive infections in patients with to beta-lactam antimicrobials ► When antibiotic-associated colitis fails to respond to metronidazole, or if it is severe and life threatening (PO Vancomycin only) ► Prophylaxis § AS recommended by the American Heart Association, for after certain procedures in patients at high risk for endocarditis § Surgical procedures involving implantation of prosthetic materials or devices at institutions with a high rate of infections due to MRSA or MRSE § Patients with severe Vancomycin

► Loading Dose needed? § Seriously ill patients and patients with complicated infections § Morbidly obese patients (fill extravascular compartment rapidly) § 25-35 mg/kg x1 (actual body weight) ► Determine Maintenance Dose: § 15-20 mg/kg IV Q12 hours § Use actual body weight § Higher end of dosing range for CNS, endocarditis, osteomyelitis ► Determine Interval § Adjust frequency for renal function § CVVHD Dosing: 1 g IV q 24 hr § Intermittent dialysis: Administer doses after dialysis session ► Oral formulation NOT absorbed; use for local GI tract , ie. Clostridium difficile

Checking Vancomycin Troughs

► Trough: measure for efficacy § Draw 30 minutes before the 4th dose in patients with normal renal function § Patients on HD-draw a level after each dialysis session § Intermittent Hemodialysis: ► During a typical 4 hr session, 30-50% of vanco is removed ► Drawn a level 4-6 hrs after completion of dialysis to allow for redistribution ► Trough Targets § Target trough: 15-20 mg/L for , endocarditis, meningitis § 10-15 mg/L most other sites ► Oral formulation NOT absorbed; use for local GI tract infection, ie. Clostridium difficile

Vancomycin

► Adverse Effects § Eosinophilia, reversible , thrombocytopenia § Ototoxicity (associated with high peaks) § Red Man’s Syndrome ►Not an allergy, but a release of histamine due to the rate of the infusion ►SOLUTION: Infuse the drug over a longer time period (2 hrs instead of 1hour) Linezolid

► Effective against MRSA ► Indicated to treat infections due to Gram positive organisms ► Dose: 600 mg q12 hrs. for both IV and PO § high ► Monitoring § Thrombocytopenia (black box warning) § Peripheral neuropathy ► Drug interactions § Linezolid has MAO-I-like properties § Interaction with SSRI, TCAs ► Serotonin syndrome: fever, mental status changes, tremors ► No renal adjustment ► Expensive: $82/tablet Daptomycin

► Spectrum of activity: Gram positives § i.e MRSA ► Poor activity in the lungs due to inactivation § DO NOT use for pneumonia ► IV only ► Adverse effects: § at high doses, monitor CPK ► Adjust dose for renal function Extended-Spectrum PCNs + ß lactamase Inhibitor

► Zosyn (pipercillin/tazobactam) § Coverage: Most Gram positives, Gram negative including Pseudomonas § Anaerobic coverage ► Dose: 4.5 g IV with frequency based upon renal function ► CVVHD: 4.5 g IV q8 ► Adverse Effects: § Thrombocytopenia, lowers seizure threshold, 4th Generation

► Cefepime § Gram Positive and Gram Negative coverage § Covers Pseudomonas ► Dosing: § Serious systemic infection 2 g IV q12 § Other infections (pneumonia) 1 g IV q12 § **Frequency is based upon renal function** ► CVVHD: 1 g IV q12h ► Adverse effects: § Diarrhea, thrombocytopenia, lowers seizure threshold

Ceftaroline fosamil

► 5th generation cephalosporin ► Non-formulary restricted requiring Antibiotic Management Program or ID/ P&T Chair Approval (as per institution policy) ► is a semi-synthetic prodrug of ceftaroline, a broad- spectrum cephalosporin and the first available beta-lactam to demonstrate bactericidal activity against resistant aureus (MRSA). ► Ceftaroline inhibits bacterial synthesis by binding to penicillin binding (PBPs), leading to inhibition of bacterial cell wall synthesis.1 ► Ceftaroline has improved activity against MRSA due to increased affinity for PBP 2a.2 Ceftaroline fosamil

► Non-formulary approvable uses may include: § Alternative for complicated skin and skin structure infections: ► (including MSSA and MRSA), pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumonia and Klebsiella oxytoca ► when other options are not appropriate due to organism resistance, drug allergy or adverse events. (1B) § Alternative for community acquired bacterial pneumonia with a PORT score III-IV due to: ► (including cases with concurrent bacteremia), Staphylococcus aureus (MSSA isolates only), Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli. ► when other options are not appropriate due to organism resistance, drug allergy or adverse events. (2A) ► Data are currently insufficient to support the use of ceftaroline fosamil for the treatment of bacterial pneumonia due to methicillin resistant Staphylococcus aureus (MRSA). Ceftariline fosamil

► Usual dosage range: IV: 600 mg every 12 hours ► Indication-specific dosage: IV: § Pneumonia, community-acquired: 600 mg every 12 hours for 5-7 days § Skin and skin structure, complicated: 600 mg every 12 hours for 5-14 days ► Adjust dose in renal impairment § CrCl >50 mL/minute: No dosage adjustment necessary. § CrCl >30-50 mL/minute: 400 mg every 12 hours § CrCl 15-30 mL/minute: 300 mg every 12 hours § CrCl <15 mL/minute: 200 mg every 12 hours § ESRD patients receiving hemodialysis: 200 mg every 12 hours; dose should be given after hemodialysis on dialysis days Aztreonam

► Aerobic Gram negatives only ► Pearls: § Many hospitals with resistant organisms, not good empiric choice ► UPMC susceptibilities § Pseudomonas only 56% § Acinetobacter 0% ►Consider double coverage until sensitivities are available § Very low cross-sensitivity with ß-lactams ► Can be useful in allergy situations ► Time-dependent killing ► insufficiency - decrease dose, maintain interval ► Adverse effects: Rash, diarrhea, thrombocytopenia Aminoglycosides

IV PO ► Gentamicin ► Neomycin ► Tobramycin § Not sig. absorbed ► Amikacin § Used for hepatic encephalopathy ► Streptomycin (IM)

Aminoglycosides

► Gram Negative activity ► Synergy with a Beta Lactam for Gram Positives § Endocarditis ► Common ADEs: § Elevated trough concentrations ► Otoxicity ► Nephrotoxicity § Elevated Peak concentrations ► Neuromuscular blockade § Concomitant use of NMB, myasthenia gravis, hypocalcemia ► Narrow therapeutic window § Monitor “levels“ ► Especially with changing kidney function since eliminated unchanged in the urine Dosing ► Extended interval dosing § Once daily dosing for gentamicin & tobramycin § For gram negative infections § Developed to maximize killing due to ► Concentration dependent killing ► Post Antibiotic effect § Less toxicity ► Gentamicin & tobramycin doses: 7 mg/kg § Dosing weight to use: ► Smaller weight of Ideal vs. actual ► Use the adjusted BW if obese § In renal insufficiency: maintain dose, increase interval with kidney insufficiency ► Narrow therapeutic window drug/ Monitoring levels needed: § Utilize Hartford nomogram § Target Trough <2 mcg/ml Hartford Nomogram

► Use nomogram to assess frequency of dosing § 1. obtain a random level 6-12 hrs after administration § 2. Plot level on the nomogram § 3. Determine resultant frequency ►Note: renal function must remain ►Obtain a trough before redosing to ensure correct frequency Hartford Nomogram (for gentamicin and tobramycin 7mg/kg, not amikacin)

Antimicrob Agents Chemother. 1995;39:650-5. Agents Major Fungi

► Candida § 4th common cause of nosocomial § Crude mortality of 39% with attributable mortality of 14.5-49% § Emergence of resistant C. albicans and a shift to less susceptible or resistant non-C. albicans species ► Aspergillus ► Cryptococcus

► Azoles § Fluconazole, voriconazole, posaconazole, Itraconazole, ► Eichinocandins § Caspofungin, mycafungin, anidulafungin ► Polyenes § Amphotericin B deoxycholate, Lipid-based amphotericin ►Significant toxicities (renal, infusion reactions) ► Flucytosine Antifungal Activity

Fungus Flu Vori Posa Eichino Polyene C. albicans +++ +++ +++ +++ +++ C. glabrata +/- + + +++ ++ C. tropicalis +++ +++ +++ +++ +++ C. parapsilosis +++ +++ +++ ++ +++ C. krusei - ++ ++ +++ ++ A. fumigatus - +++ +++ ++ ++ A. flavus - +++ +++ ++ ++ A. terreus - +++ +++ ++ - C. neoformans +++ +++ +++ - +++ Fluconazole

► Favorable pharmacokinetic and safety profile ► Emergence of resistant C. albicans and less susceptible/ resistant species (C. glabrata or C. krusei) ► Dose reduction in renal dysfunction § Crcl <50ml/min; administer 50% of dose § Hemodialysis: 50% of the dose is removed by hemodialysis, administer dose after each dialysis treatment ► Drug Interactions § Strong inhibitor: CYP2C9; 2C19 § Moderate inhibitor: CYP3A4 § Weak inhibitor: CYP1A2 Caspofungin

► Echinocandin: semisynthetic antifungal lipopeptides ► Many Candida species are susceptible: § C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, Candida famata, Candida rugosa, and Candida stellatoidea ► Dosage: § 70mg on day 1 then 50 mg/day § Moderate hepatic insufficiency ► 70 mg on day 1 then 35 mg/day ► Not a CYP450 substrate (limited DDIs) Major Interactions

► Warfarin - likely all antimicrobials § metronidazole, SMX/TMP – result in ↑ INR § rifampin, – result in ↓ INR ► Immunosuppresants – azole antifungals § Azoles inhibit CYP 3A4 metabolism of ► Divalent cations – oral fluoroquinolones § Ca++, Mg++, Fe++, Al++ bind and ↓ oral FQ absorption ► Induce – rifampin, nafcillin