Notes for IDWeek 2016 Day 4

7am on a Saturday in New Orleans. #hardcore

Antibiotic Dosing in Special Populations

Critically Ill

• abx dosing more difficult because you’re not just trying to exert pharmadynamic effects on the patient, you are actually targetting the pathogen
  • more difficult to monitor than, say, blood pressure
• plasma concentrations are surrogates, and not always a great representation of tissue
• Vanco was rushed through clinical development, 2gm/day was considered “effective and minimally toxic” (1958)
• cefotaxime breakpoints was originally decided based on peaks except it’s not a concentration dependent drug
• polymixin B - CrCl dependent dosing but it’s not elminated renally
• hydrophilic abx: lower Vd, mostly renally cleared, low intracellular penetration
• lipophilic: higher Vd, mostly hepatically cleared, good intracellular penetration
  • see slide for some examples
• changes in critically ill:
  • imparied absorpation -> decreased AUc
  • capillary leak -> increased Vd,. decreased plasma concentration, delyayed distribution
  • end-organ damage -> decreasee clearance, increased AUC
    • pharmacists good at lowering dose of drug, but generally less good at bumping doses when appropriate.
  • hypoalbuminemia: increased free fraction, variable effects
    • only imporant for protein-bound drugs
  • augmented clearance -> decreased AUC and drug exposure
• Roberts JA. Clin Pharmacokinet 2006;; Udy AA clin pharmacokinet 2010; Uildemolis M; CHEST 2011
  • see slide in the lecture; shows common changes for different critically ill states
• Augmented renal clearance
  • GFR >150, 160 (different definitions)
  • caused by a variety of fators in multiple states (eg sepsis, trauma) has increased cardiac output; we add fluid and pressors, things get pushed through quickly
  • no renal dosing guidelines for things like CrCl 150
  • Current formulas available for CrCl are terrible at calculating augmented. Baptista JP Critical Care 2011
    • Cockcroft gault was actually the best, but all were a severe underestimate
• Roberts JA et al In J Antimicrob Agents 2010:
  • 30 bed ICu over 11 months, adjuted abxx based on twice weekly stead state troughs
  • had to increase doses 50% of the time from the initial doses physicians were ordering
  • 72% did not achieve target endpoints
• DALI study: defining antibiotic levels in intensive care patients
  • Roberts JA et al Clin Infect Dis 2014
  • large study doing similar to the last one but with multicenter and way more patients
  • up to 500 fold difference in unbound concentrations of abx at both sampling points
  • 16% did not achieve target and this was associated with clinical failure
• summary: Roberts JA, Lipman J. Clin Pharmacokinet 2006 (table in slides)
• should probably be loading patients when they have an increased Vd

Obesity

• increased failures: low relative dosing or effects of obesity itself?
• antibiotic use in early age is associated with obesity due to changes in the microbiome
• absorption - not significantly modified
• distribution: hydrophilic drugs should not be reatly incluenced as only 5% of cardiac output is blood flow into fat (maxes out)
• Vd increases generally occurs
• Metabolism: changes not well defined in obesity
• Elimination: higher glommerular planar surface area
• Pk effects of obesity are hard to predict in infected, ill patients
  • sometimes decreases likelyhood of target attainment but sometimes increases it too (depends on drug)

CRRT

• a lot of dosing literature is out of date due to improvments in CRRT machines etc; we underdose a lot of drugs
• Hemofiltration -> Convection
  • activvel removal of solutes and drugs by pump-drive pressure gradient
  • higher propensity to remove larger drugs
  • independent of concentration gradients or molecular drugs
  • Sieving coefficeint can be helpful if you have it
• Hemodialysis -> diffusion
  • Passive moment of substances down concentration gradients across semipermiable membrane
• CVVH = convection, CVVHD mostly diffiusion (little convection), CVVHDF = lots of both => more drug removed than expected
• Dose of CRRT -> factors effluent flow and duration of CRRt; most important variable
• Blood flow rate and surface area of the filter have low impact on drug concentration
• Filter material: where sieving coeffecient comes into play
• Protein binding -> only unbound drug removed by CRRt
• increase in Vd in CRRT: larger loading dose needed, but decreased efficacy of CRRT removal
• Heintz BH. Pharmacotherapy 2009: amazing reference paper
• Beumier M, Crit care 2014: looked at non renal dose adjusted abx in CRRT patients
  • only 10% proportion of inadequate concentrations
  • trade off, 53% had very high levels
  • how do we know what an actual toxic level is for a beta lactam? they tend to be relatively safe agents in terms of dose related toxicity so aiming for efficacy targets may be more appropriate
• most CRRT dose studies assume 1-2L/hr and minimal residual function; check on your patients, often it’s running more like 2-3 L/hr and pt may have some residual renal function
• consider loading doses! esp in drugs we know will be cleared well (like low protein bound etc) and possibly more aggressive maintenance doses
• moving target: CRRT is constantly changing (like while a patient is on it), need to constantly reassessing the dose adjustments

Strategies

• Individualized dosing, determined by physiological characteristics that may affect PK
• Scaglione F et al Eur Respir J 2009: Pk/PD optimization on the patient level in HAP
  • real time TDR for several abx, made dose adjustments in ~40% of the patients in the study (pts were underdosed)
  • pts who got the adjustments had better clinical and microbiological outcomes
• Roberts JA lancet infect Dis 2014: Bayesian calculations
• Presenters do not recommend dose capping for vanco; will use 2-2.5 g loading doses (sometimes divided LD strategies) and one has gone up to 6g daily for vanco
• Also do not dose cap for daptomycin (use TBW)
• recommended max is 600 q8h for ceftaroline but have used 900 for 450lb pt

Use of New Antibiotics: FDA Indications and Beyond

• www.pewtrusts.org -> great overview of current abx pipeline
• 37 abx in development bt only 11 in phase 1
• 6 in phase 3 for gram neg infections

**Gram Positives **

• Oritavancin
  • SOLO-2 trial. ABSSSI, gram positive only; possible warfarin DI due to cyp interaction but recent study shows no issue as long as you wait 12 hours after oritavancin dose
  • several trials ongoing
• Dalbavancin
  • some enterococcal activity; two doses 1 week apart, or one single 1500mg dose (new single dose study)
  • may have utility in OPAT
  • case reports in bacteremia but no real studies
  • being studied for CAP
• Tedizolid
  • ongoing study for HAP/VAP; 50% enrolled. once a day for 7 days vs linezolid standard dose x 10 days
• Solithromycin
  • Fluroketolide with boroad spectrum
  • IV/PO
  • strep pneumo; atypicals; MSSA/MRSA; h influ, n gonorrhea
  • SOLITAIRE-ORAL study: PO vs moxifloxacin for CABP. Lancet 2016
    • 800mg day 1, 400mg day 2-5, placebo day 6-7
    • managed to isolate a baseline lung pathogen in 50% of the patients; surprisingly high percentage found atypical pathogens
      • serologic testing may overestimate atypical prevalence
  • SOLITAIRE-IV : same drugs and study type. sicker patients
    • File et al CID 2016
    • Saw more infusion related adverse events, but few led to discontinuation
    • LFT abnormalities found too
    • was hard to gauge QTc differences but seemed better than Moxifloxacin
  • studies still undergoing including for gonorrhea
  • concern giving history with telithromycin (was pulled post-marketing for hepatotoxicity)
• Fusidic Acid
  • Craft et al CID 2011
  • orally bioavailable, currently in phase 2 ABSSSI vs linezolid
  • open label study underway for prosthetic joint infection
  • concern about resistance and need for combination therapy
• Iclaprim
  • TMP like dihydrofolate reductase inhibitor
  • was around in the early 2000s
  • new IDweek poster showing in vitro activtiy vs clinical HAP
  • phase 2 HCAP study vs vancomycin
  • REVIVE studies - for ABSSSI
• Lefamulin
  • Pleuromutilin Antibacterial
  • Concentration depent
  • novel MOA - protein synthesis inhibitor
  • Phase 2 for ABSSI vs vancomycin
  • LEAP trials; phase 3 underway vs moxi for CAP
  • exploring HAP, prosthetic joint, gonorrhea
• Delfloxacin (Melinta)
  • broad spec quinolone with MRSA activity
  • oral biovailbility, broad spec, efficacy in obese patients
  • no QTc prolongation observed, less side effects - no LFT, glucose changes, etc
  • Studied 300mg IV BID vs vanco/aztreoname phase 3 ABSSSI
  • new study for this IDWeek: delafloxacin IV then 450mg PO BID vs vanco/aztreoname phase 3 ABSSSI
  • NDA filed for ABSSSI (phase 3 complete); CAP study slated to start this winter
• Omadacycline
  • minocycline derivate, active against tetracycline resistant pathogens
  • potentially active against MRSA
  • ABSSSI:100mg IV / 300mg PO vs linezolid, comparable
  • infusion-related extravasation found, otherwise just nausea
  • recruting for CAP vs moxifloxacin
• still need better data for VRE
  • McKinnell and Arias, CID 2015: evidence gap for current GP abx

Gram Negatives

• new beta-lactamase inhibitor combos hit key serine beta-lactamases inc class A(esbl, KPC) class C(ampcC)
• none hit Class B metallo beta-lactamases(NDM-1)
• ceftolozane/tazobactam
  • activity against pseudomonas, much better breakpoints than ceftaz or piptaz
  • about 50% of mero/ceftaz resistant orgs will be resistant to zerbexa
  • MDR Kleb : sucks compared to mero
  • ESBL: better than piptazo or ceftaz but not as great as mero
• ceftaz/avibactam:
  • pseudo activity is dependent on low efflux versions of the bug
  • govers KPC, enterobacteriscia
  • approved for cUTIs on phase. date, phase 3 is completed and under FDA review
  • phase 3 trial for cIAIAs (cid 2016), nosocomial pneumonia completed but not published
  • compared against other drugs in Lancet 2016 but didn’t look at CRE
  • Dosed as a prolonged infusion (2g q8h over 2 hrs each)
• Meropenem-Vaborbactam
  • ESBL, CRE -> activity similar to plain mero against non CRE
  • well matched PK properties of mero and vaborbactam
  • MIC vs pseduo,acinetbacter same as mero but may work better as high dose/prolonged infusion
• Plazomicin
  • Aminoglycoside designd not to be affected by major aminoglycoside modifying enzymes
  • Better activity than amikacin against MDR, ecloi but not improved for pseudomonas
  • Active vs CRE but not in NDM versions
  • Some posters here regarding TDM- similar toxicity etc to other aminoglycosides
• Eravacycline
  • Fluorotetracycline
  • Similar to tigecycline
  • Potent gram +ve and -ve coverage; 2-4 fold more potent than tige
  • Covers kleb, acintobacter; anaerobes
  • Orally bioavailable
  • trials in cIAI (vs erta), planned vs mero; cUTI
• See slide: statistically powered NI trials for New Gram Negative Agents provide Important Data
  • Levo R at baseline for UTI in the ceftolozane study
  • Decreased CTOl.TAZZO efficacy in pts with crcl 30-50 in the cIAI study vs mero
    • same with the ceftaz-avi study
    • may have been renal dosed but then renal function rapidly recovered and dose wasn’t bumped up
    • renal dose guidelines from manufacturer are based on simulations
  • Eravacyclin vs Levo in cUTI -> missed endpoint, study showed that the patients who were stepped down to the PO eravacycline had clinical failure. Company working on a new PO formulation to try again
• there are ongoing trials for treatment of CRE; can be difficult because you have really sick patients and you really need to widen your inclusion criteria
  • TANGO 2, CARe, RESTORE-IMI-1 (mero-vabor, plazomicin, imi/cilastatin/relebactam)

Antifungal Agents

• Posaconazole and Isavuconazole
• broad spectrum; cover mucorales (historically only have amphoB)
• Posaconazole: - originally PO posa required high fat meals and stuff for absorption. 2013-2014 came out with a adelayed release that gives once daily dosing and better bioavailability
  • tablets better than the oral suspension for blood levels
  • approved for oropharyngeal candidiasis, prophylaxis of aspergillus and candida
  • non FDA indications: aspergillosis, mucormycosis, scedosporium and fusarium
    • voriconazole is first line for aspergillosis but toxicitys can limit its use (like photopsia, hallucinations, photosensitivity, skin carcinogensis, fluorosis)
• Isavuconazole:
  • IV and PO, water soluble but does not require cyclodextrin for solubilization so don’t need to adjust for renal failure
  • QTc Interval shortening - WHA!? - not yet sure of clinical impact
  • FDA for invasive aspergillosis