Ho Stanford 2019 – New Antibiotics

Ho Stanford 2019 – New Antibiotics


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


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


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


  • 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


  • 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


  • 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


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


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


usually related to conditioning chemo regimen




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


  • 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)


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


      • 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


  • 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


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



    • 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
    • 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
    • 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 1mg/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


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


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


  • 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).