MICU Antibiotics and Associated Drug Interactions

MICU Antibiotics and Associated Drug Interactions

Resistant Bacteria 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 Pseudomonas aeruginosa Acinetobacter Klebsiella pneumoniae ESBL E.Coli ESBL Staph Aureus MRSA Enterococcus faecalis & faecium VRE

Antibiotic Management Program (AMP) Patient safety initiative to address: The infections related to C. difficile Increasing antimicrobial resistance 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 Linezolid Ceftriaxone Ceftazidime Aztreonam Daptomycin Clindamycin Meropenem Imipenem Oral Vancomycin unless you fill out a C.diff order set

Not Restricted in the ICU Vancomycin Zosyn (piperacilin/tazobactam) Cefepime 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 microorganisms Gram positive infections in patients with allergies 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 endocarditis 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 penicillin allergy

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 infection, ie. Clostridium difficile

Checking Vancomycin Troughs Trough: measure for efficacy Draw 30 minutes before the 4 th 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 pneumonia, 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 neutropenia, 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 bioavailability 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: Myopathy 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, diarrhea

4 th Generation Cephalosporin 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

5 th generation cephalosporin Ceftaroline fosamil Non-formulary restricted requiring Antibiotic Management Program or ID/ P&T Chair Approval (as per institution policy) Ceftaroline fosamil is a semi-synthetic prodrug of ceftaroline, a broadspectrum cephalosporin and the first available beta-lactam to demonstrate bactericidal activity against methicillin resistant Staphylococcus aureus (MRSA). Ceftaroline inhibits bacterial cell wall synthesis by binding to penicillin binding proteins (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: Staphylococcus aureus (including MSSA and MRSA), Streptococcus 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: Streptococcus pneumoniae (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 Kidney insufficiency - decrease dose, maintain interval Adverse effects: Rash, diarrhea, thrombocytopenia

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

Gram Negative activity Aminoglycosides 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.

Antifungal Agents

Major Fungi Candida 4 th common cause of nosocomial bloodstream infections 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

Antifungals Azoles Fluconazole, voriconazole, posaconazole, Itraconazole, ketoconazole 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, nafcillin result in INR Immunosuppresants azole antifungals Azoles inhibit CYP 3A4 metabolism of tacrolimus Divalent cations oral fluoroquinolones Ca++, Mg++, Fe++, Al++ bind and oral FQ absorption Induce drug metabolism rifampin, nafcillin