Ho Stanford 2019 – New Antibiotics

Ho Stanford 2019 – New Antibiotics

2017

  • delafloxacin (fluoroquin)
  • mero-vaborbactam (beta-lactam/beta-lactamase inhib)
  • letermovir (for CMV) (PREVYMIS) *available on Stanford formulary

2018

  • plazomicin (aminoglycoside) (ZEMDRI) *available on Stanford formulary
  • eravacycline (tetracycline)
  • omadacycline (tetracycline)

2019

  • imipenem/cilastatin/relebactam (beta-lactam/beta-lactamase inhib)

ANTI-MRSA AND +/- VRE

  • tedizolid (SIVEXTRO) *available on Stanford formulary
  • oritavancan
  • dalbavancan (DALVANCE) *available on Stanford formulary
  • ceftolazone/tazobactam
  • ceftazidime/avibactam

Lefamulin (XENLETA)

  • FDA-approved for IV and oral treatment for CAP
  • not active against Enterobacteriaceae or Pseudomonas
  • in vitro/in vivo against Strep pneumoniae, H flu, mycoplasma pneumoniae, chlamydia pneumoniae, Legionella, and MSSA

Cefiderocol (FETROJA)

  • broad in vitro activity against gram negatives -> including CRE
  • active against carbapenem-resistant stuff -> CRE, carbapenem-resistant Pseudomonas, carbapenem acinetobacter, and Stenotrophamonas (which is usually sens to levaquin and bactrim)
  • interestingly, FDA-approved for UTI but clearly this is a weird population <- this happens b/c they can enroll large numbers of pts (those w/ UTI) for these studies

Plazomicin (ZEMDRI)

  • similar bucket of coverage as FETROJA
  • a “next-generation” aminoglycoside
  • FDA-approved for complicated UTI (again, b/c this population has studies?)
    • Enterbacteriaceae who have limited treatment options -> susceptible E coli, Klebsiella, Proteus, Enterobacter cloacae)
  • caution with ototoxicity/nephrotoxicity -> if CrCl is low, should do therapeutic drug monitoring
  • has good synergism with colistin, mero-, and fosfomycin against gram neg bacteria (particularly those VIM-1 and KPC-producing gram negatives)

*available on Stanford formulary

Cefepime-resistant Enterobacter (DOI: 10.1128/AAC.01477-15 and https://doi.org/10.1093/cid/cit395)

  • there is the notion that there are ampC-producing, ESBL-producing Enterbacter cloacae species -> we often treat them with cefepime or a carbapenem
    • in vitro data suggests that cefepime retains activity against these ampC producing Enterobacter

TETRACYCLINES

  • historically, chlortetracycline was subsequently manufactured to be tetracycline
  • then, in the 1970s, the field developed doxycycline and minocycline
  • then, in 2005, the production of tigecycline was performed -> broad spectrum of activity with gram positive and gram negative coverage

Eravacycline (XERAVA) (10.1007/s40265-016-0545-8)

  • a synthetic tetracycline with widened activity
  • more potent than tigecycline
  • effective against ESBL-producing Enterbacteriaceae and carbapenem-resistant Acinetobacter baumanii
  • not active against Pseudomonas or Burkholderia
  • kind of like a better version of tigecycline
    • more potent against gram positives and gram negatives than tigecycline -> not great against Pseudomonas
  • good for complicated intra-abdominal infections
  • don’t need to adjust for renal impairment

Omadacycline (NUZYRA)

  • a first-in-class, oral drug -> aminomethylcycline
  • available as PO or IV
  • activity against the gram positives, gram negatives, and atypical
    • of note, good against the tetracycline-resistant bacteria
  • FDA-indicated -> community-acquired bacterial PNA and skin/soft-tissue infection
  • no adjustment for renal or hepatic impairment

MRSA-ACTIVE ANTIBIOTICS

  • vanco
  • telavancin
  • dalbavancin
  • oritavancin^
  • daptomycin^ (not great for lung infections nor CNS infections—use linezolid)
  • ceftaroline
  • linezolid^
  • tedizolid^
  • quinupristin-dalfopristin^ (but not active against E. faecalis)
  • eravacycline^
  • omadacycline^
  • lefamulin^

^indicates VRE activity as well as MRSA activity

Delafloxacin (BEXDELA)

  • new, improved fluoroquinolone which is active in acidic environments (abscess/empyema, vaginal area, urine) -> FDA-indicated for CAP, skin/soft-tissue infection
    • watch LFT elevations
  • bactericidal like other fluoroquinolones
  • more active against MRSA
  • gram positive activity -> MRSA, MSSA, Strep pneumoniae, Streptococcus, Enterococcus spp
  • gram negative activity -> H flu, Moraxella catarrhalis, Neisseria meningitides, Neisseria gonorrhoeae, Enterobacteriaceae, Pseudomonas
  • anaerobes -> Bacteroides spp, Prevotella spp, C diff, Clostridium perfringens
  • intracellular -> Mycoplasma spp, Ureaplasma spp, Chlamydia spp
  • mycobacteria -> TB

Screen Shot 2019-12-17 at 10.59.34

COMBOS THAT COMBAT THE BETA-LACTAMASE

Ceftolozane/tazobactam (ZERBAXA)

  • active against the ampC and ESBL producers -> i.e. ESBL Pseudomonas
    • not great against anaerobes and gram positives
  • FDA-indicated for
    • complicated UTI/pyelo, complicated intra-abd infection (w/ flagyl)
    • has been compared with meropenem for intra-abd infection

*available on Stanford formulary

Ceftazidime/avibactam (AVYCAZ)

  • similar spectrum of activity as ZERBAXA
    • not great against gram positives and anaerobes
  • also, FDA-indicated for complicated UTI or complicated intra-abd infection w/ flagyl

*available on Stanford formulary

Meropenem-vaborbactam (VABOMERE)

  • the vabo inhibits many of the beta-lactamases -> class A, class C and some class D beta-lactamases
    • the class A effect is seen with the restored meropenem activity against Enterobacteriaceae that produce the class A, serine carbapenemase KPC.
    • i.e. VABOMERE can now be used for KPC-producing Enterobacteriaceae
  • FDA-indicated for complicated UTI, pyelonephritis

Rezvani Stanford 2019 – Hematopoietic Cell Transplant

REZVANI STANFORD 2018 – HEMATOPOIETIC STEM CELL TRANSPLANT (HCT)

Updated 12/18/19

Autologous – own cells

Allogeneic – someone else’s cells

MCC dx is Multiple Myeloma

  • these days we mostly do auto-transplants; not allo’s <- AML and ALL and MDS are the biggest indications for the allo’s

AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANT (less risky/less likely to be ICU) -> point is that you’re removing their cells to allow for much much higher chemo tx than would otherwise tolerate then giving them their cells back

  • remember the actual “taking the cells and giving them back” doesn’t do much -> it’s the ability to give them really really high chemo tx that they get while you take out the blood cells prior to giving them back
    • step 1) collect cells via IV
    • step 2) store them frozen
    • step 3) they get high dose chemo -> they get pancytopenia and mucositis
    • step 4) they get the cells back -> takes 10-14 days to engraft
  • bone marrow failure -> dose limiting the myelo-toxic doses via taking the stem cells out temporarily
    • can think about it as “high dose chemo”
  • need to hit up the “right” pt population -> choosing the population where the curative dose of chemo would lead to death via chemo <- so take out the cells temporarily
  • risk for MDS which is roughly 5% at 10 years out

multiple myeloma -> remember that autologous xplant isn’t curative; just prolonging remissions

  • there’s no way to avoid contamination of stem cell product w/ tumor cells

Lymphomas -> autologous xplant could be curative in this case

leukemias are less for autologous HCT b/c less curative

*bone marrow bx before and after collecting the cells

AUTO HCT -> mobilize via G-CSF, chemo, collection via apheresis, storage in DMSO/freezer

  • OP process
  • pancytopenia, mucositis side effects
  • conditioning chemo
  • median time to engraftment = 10 days
  • long term side effects -> MDS risk 5% at about 10 years

ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT -> point for allo- as opposed to auto- is that you’re relying on the donor’s alloimmune attack against the residual malignancy. This is a form of immunotherapy; whereas the autotransplant above is form of chemotx.

  • different principle than auto
  • you’re getting the entire donor’s immune system <- that means you’re getting the donor’s entire immune system
    • “graft vs. tumor effects” whereby the alloimmune attack by donor cells on residual malignancy
  • main criteria is HLA matching
    • first choice = HLA-identical sibling
    • second choice = HLA-matched unrelated donor from National Marrow Donor Program

age limit in the unrelated donors, the cut off is about 60 yo -> ethics reasons

cord blood

  • collected from placenta at birth
  • rich in hematopoetic cells but low in T cells
  • b/c immunologically naive, you have greater tolerance for non-HLA matching…

can match peeps who are matched at 9/10 rather than 10/10 but your risk for GvHD goes up

umbilical cord blood has HSC

  • since these cells are more immunologically naive, you can get away with more HLA mismatching and still use them
  • typically you use two units and one will usually engraft -> 20 years ago, rates of non engraftment were very high b/c only used one unit

haploidentical family donor -> someone who shares half your HLA type

  • HLA disparity leads to GvHD
  • not having a fully-matched donor (i.e. when you’re haplo-identical), you have risk that the immune cells won’t fully attack the malignancy; there’s some concern that you may be at risk for long-term relapse

*few direct head-to-head comparisons with conditioning regimens

  • common elements -> total body radiation (TBI…small doses) and chemotherapy agents
  • “myeloablative” is the name of the game -> esp with autologous HCT, you’re using high dose during the conditioning regimen since you’re depending on the chem to cure the disease
    • carmustine, etoposide, cytoxin, etc are the common ones for myeloablative tx

concept of the allogenic HCT is that you’re relying on the immune GVT effect from donor cells

  • so conditioning regimen can be less “myeloablative” than the autologous
  • “reduced intensity,” “mini,” “non-myeloablative,” “reduced toxicity,” or “sub-myeloablative” terms
  • the more intensive the conditioning regimen = more likely to eradicate the disease = but you’re more likely to get side effects

POST TRANSPLANT COMPLICATIONS

usually related to conditioning chemo regimen

mucositis

fevers

pancytopenias

SOS – sinusoidal obstruction syndrome -> liver complication of obstruction from chemo

  • usually in the first couple of weeks post-TXP
  • TTP RUQ, ascites
  • can get hepatorenal syndrome

GvHD

  • allogenic tx
  • donor cells usually attack the malig; when it spills over and attacks the recipient, that’s GvHD
  • acute GvHD is usually within first 90d after transplant
  • skin rash
    • can try to get skin or EGD bx of GI tract
      • skin-only GVHD or upper-gut GVHD -> they tend to do well
      • lower-gut GVHD is dangerous/has large vol diarrhea usually
  • N/V/D
  • nonspecific rashes
  • ultimately, it’s a clinical dx; however, can try to use skin or endoscopic bx -> need to differentiate endoscopic dx (GvHD vs. CMV)

TREATMENT FOR ACUTE GVHD

  • prednisone -> usually 1-2 g/kg daily
    • can usually taper down after couple of weeks

STEROID-REFRACTORY GvHD is dangerous

      • 5-15% of people have steroid-refractory GvHD -> often fatal
      • once you destroy the crypt cells/gut stem cells, the gut epithelium is unlikely to repair
      • bacterial translocation/protein loss/malnutrition

IMMUNOSUPPRESSION

  • tacro (calcineurin inhibitor)
  • cyclosporin
  • HOWEVER, don’t need to be on immunosuppression lifelong -> donor cells will typically develop tolerance -> immunosuppression pulled back about 6w after HCT typically
  • GvHD is seen in 20-50% of patients
  • e.g., Stanford pt with initial tacro, but that was stopped 2/2 AKI; and, b/c of AKI they were never started on methotrexate
    • however, they were then started on mycophenolate mofetil (MMF) with reduced dose 2/2 AKI as well as sirolimus

CHRONIC GvHD (usually 90-100 days later) -> looks like Lupus or autoimmune diseases

  • various degrees of severity -> some mild, some debilitating

CAUSES OF DEATH

usually the primary problem that brought them in (i.e. not the GvHD) is the cause of death in these people

COMPLICATIONS

INFECTIOUS

  • ASPERGILLUS
    • suspicious looking lesions -> mold ppx
    • bronch
    • “halo sign” -> hazy infiltrate around fungal nodule
    • crescent sign -> cavitary lesion w/ air pocket around it
  • optimal tx is unknown -> concept seems to be keep them on mold control agent until they’re off their immunosuppression <- steroids seem to be arisk for this
    • voriconazole
    • posaconzaole
  • CMV
    • monitored weekly
    • MCC viral pathogen in BMT
    • 50% of BM pts have CMV reactivation (i.e. most people have been exposed to CMV in their life)
    • rely on timely/monthly CMV PCR
    • we probably overtreat for CMV
    • CMV pneumonitis is really high mortality
  • DIFFUSE ALVEOLAR HEMORRHAGE
    • in the ddx when there’s respiratory failure
    • usually in the first month after transplant
    • p/w progressive resp failure
    • very uncommon in autologous HCT
    • much more common after allo HCT
    • CXR similar to any diffuse alveolar disease -> b/l fine reticular opacities -> pulm edema/ARDS
    • bronch dx and then BAL returns with increasingly bloody lavages
      • tx with high dose steroids -> belief is that donor cells are causing inflammation
  • GI PCR panel
    • At Stanford, tests for Campylobacter, Plesiomonas, Salmonella enterica, Shiga-like toxin-producing E coli O157, Shigella, Vibrio cholerae, non-cholerae Vibrio species, Yersinia enterocolitica, Cryptosporidium, Cyclospora cayetenesis, Entamoeba histolytica, Giardia lamblia, Adenovirus, Astrovirus, Norovirus, Rotavirus, Sapovirus
  • Respiratory PCR panel
    • At Stanford, tests for Flu A, Flu B, RSV, Parainfluenza viruses 1-4, metapneumovirus, Rhinovirus/Enterovirus, Adenovirus, Coronavirus, Chlamydi pneumoniae, mycoplasma pneumoniae
  • CMV PCR quantitative
    • tests plasma
  • HSV 1/2 PCR
    • can look at blood or lesions if there are any
    • can look at swab/lesion, BAL, CSF, ocular fluid, or plasma
  • VZV PCR
    • can look at swab/lesion, BAL, CSF, ocular fluid, or plasma
  • AFB culture
    • lung tissue can be sent for AFB
  • Fungal culture or beta-D-glucan
    • can send lung tissue or blood
  • Viral culture and Adenovirus DNA PCR
    • can send tissue

IPS -> idiopathic PNA syndrome. This is a FIBROSING PROCESS.

    • catch-all term -> diffuse alveolar dmg
    • general term for diffuse alveolar injury for which cannot find an infection
    • multilobar opacities -> progressive hypoxic resp failure
    • usually in the first 4-6 months after HCT
    • not-great evidence, but treated w/ steroids -> usually 1g/kg glucocorticoids; sometimes they go pulse on them with 1g

BRONCHIOLITIS OBLITERANS -> how chronic GvHD presents itself. Defined by granulation tissue in the BRONCHIOLAR LUMEN.

    • they have severe airflow obstruction after allo-HCT
    • usually thought to be similar process as in lung xplant -> mismatch between the lung and the immune system
    • tx w/ inhaled and systemic steroids
    • azithro <- recent evidence that azithro could be harmful for these pts…not sure what study this was…
    • montelukast

ORGANIZING PNA (formerly BOOP) -> granulation tissue in DISTAL AIRSPACES. This is an INFLAMMATORY PROCESS.

    • many patchy infiltrates -> chest CT looks really bad out of proportion to sx
    • GGOs, nodules, bronchial wall thickening and patchy opacities

bone marrow xplant team categorizes pts at Stanford based upon their risk for ICU

Hall Principles of Critical Care 2015 – Chapter 44: Noninvasive Ventilation

Most likely to benefit – COPD or hypercapnic acute cardiogenic pulmonary edema

Caution in severely hypoxemic patients

  • Delay in endotracheal intubation should not occur because of NIPPV
  • Favorable response is usually apparent in the first 2 hours
  • Key is appropriately selecting the right patients for NIPPV

COPD

2004 Cochrane database review showed decrease in mortality, decreased intubation, and faster clinical improvement associated with NIPPV.

Dangers of inadequate ventilation

  • Transdiaphragmatic pressure generation is high -> risk of respiratory muscle fatigue

Acute cardiogenic pulmonary edema

Decreases work of breathing and improves cardiovascular function

Cardiovascular function

  • Decreases LV afterload
  • Reduces RV and LV preload

3CPO study showed that in patients with clinical dx of CPE (RR > 30, pH < 7.35, CXR w/ edema) randomized to NIPPV or standard oxygen tx had improved physiologic outcomes with NIPPV, but no difference in intubation rates and 7 and 30 day mortality.

  • Crossover – There was a high incidence of crossover (~15%) from the standard oxygen group. This could make argument that higher rates of intubation could have happened in standard oxygen group.
  • Sick patients excluded – Severely ill patients w/ need for lifesaving intervention were excluded.
  • CPAP vs. PSV+PEEP – Similar outcomes (re: intubation, mortality, clinical changes) between the two modes of NIPPV.

Hypoxemic respiratory failure

Difference between CPAP and PSV+PEEP

CPAP

  • Early benefit with dyspnea and oxygenation
  • But, no difference with ETI, mortality, or ICU LOS
  • CPAP alone not recommended in mild to severe ARDS

PSV+PEEP

  • Multiple RCTs (Martin 2000, Ferrer 2003) found benefits regarding intubation and mortality. Though importantly these studies had heterogenous patient populations with ARDS from multiple etiologies.
  • Despite some benefit seen in the studies above, there have been high rates of NIPPV failure in PNA and severe hypoxemia patients (Meduri 1996, Jolliet 2001, Domenighetti 2002, Antonelli 2001).