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

Antibiotic is stopped

3 hour PAE

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 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 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 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

4th 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

Ceftaroline fosamil ►  5th generation cephalosporin ►  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 broad-

spectrum 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

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.

Antifungal Agents

Major Fungi

► Candida §  4th 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