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 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


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).


Frat Crit Care Med 2018 – Predictors of Intubation in Patients With Acute Hypoxemic Respiratory Failure Treated With Noninvasive Oxygenation Strategy

Article Citation

Frat JP, Ragot S, Coudroy R, et al. Predictors of Intubation in Patients With Acute Hypoxemic Respiratory Failure Treated With a Noninvasive Oxygenation Strategy. Crit Care Med. 2018;46(2):208-215.

What We Already Know About the Topic

Per the FLORALI study, patients managed with HFNC appear to have better mortality outcomes than those managed with combination of HFNC and non-invasive ventilation (NIV). Furthermore, the LUNG SAFE study showed that hypoxemic patients failing NIV had higher mortality rate than those invasively ventilated. This introduces the topic of the optimal pre-intubation (i.e. noninvasive ventilation) strategy in ICU patients.

Why This Study is Important

Helps to guide the airway management for hypoxemic respiratory failure patients. Further, the increased work on patient self-induced lung injury (P-SILI) has shown that large swings in transpulmonary pressure may help characterize patients who do not do well in acute respiratory failure.

Purpose (PICO format)

In a post hoc analysis of a randomized controlled trial, ICU patients with acute respiratory failure were randomized to receive standard oxygen, HFNC, or NIV with measured outcomes of early and late predictors of intubation as well as 90 day mortality.


23 centers in France and Belgium


This analysis a post hoc look at a randomized controlled trial of ICU patients. Acute respiratory failure was defined as RR > 25 bpm, PaO2/FiO2 < 300 mm Hg and a PaCO < 45 mm Hg. Data collection was at baseline and at 1 hour post-randomization to specific oxygen strategy. Intubation criteria were predetermined and were 1) worsening respiratory failure via > 2 of criteria: RR > 40, no improvement in signs of respiratory muscle workload, copious secretions, pH < 7.35, or SpO2 < 90% for 5 min; 2) HD instability; or 3) Deterioration of mental status.

Outcome Measures

Identify early factors associated with intubation–at baseline and 1 hour after initiation of each treatment. Secondary outcome was to identify factors associated with mortality at 90 days.

Inclusion criteria

ICU patients with acute respiratory failure

Exclusion criteria

Severe neutropenia, acute-on-chronic respiratory failure, cardiogenic pulmonary edema, shock, or altered consciousness


Of the 310 patients included, most of them had moderate hypoxemia (i.e. PaO2/FiO2 ratio between 101 and 200 mm Hg). 94 patients received standard oxygen (mean gas flow ~13LPM). 106 patients received HFNC (mean gas flow 48 LPM). 110 patients were treated with NIV (mean expired tidal volume 8.7 mL/kg). 45% of the population needed intubation. For each group, independent factors predictive of intubation were as follows: standard oxygen patients – RR > 30 bpm, HFNC patients – increased HR at one hour after intiation, NIV patients – both PaO2/FiO2 ratio at one hour < 200 mm Hg and expired TV  at one hour > 9 mL/kg.

In terms of 90 day mortality, factors significantly associated were the following: standard oxygen or HFNC – SAPS II score, NIV – TV > 9 mL/kg of PBW one hour post oxygen strategy implementation.


Tempting to extrapolate these data findings to emergency department patients; though, would have caution as these are different substrates.

Conclusions of the Authors of the Study

Finding the significant factors predictive of intubation and mortality can help physicians decide airway management strategies early in the acute respiratory failure process.

Take Home Points for Us

Pay attention to certain variables like RR, HR, and expired tidal volumes when managing tenuous acute respiratory failure patients in the ICU. Realize that these variables may represent crucial pathophysiological changes portending worsened prognosis (i.e. large expired TV may represent swings in transpulmonary pressure and the resultant baro-/atelectatrauma of ARDS).

Chua Ann Intensive Care 2011 – Sodium bicarb in DKA


Chua HR, Schneider A, Bellomo R. Bicarbonate in diabetic ketoacidosis – a systematic review. Ann Intensive Care. 2011;1(1):23.

What We Already Know About the Topic

DKA is either a absolute or relative deficiency of insulin. Ketones are generated with the liver’s metabolism of free fatty acids. Accumulation of anions occurs through various mechanisms with severe dehydration as clinical manifestation. Sulphate, urate and phosphate are accumulated.

Metabolic acidemia has prompted some physicians to administer bicarbonate given the thought process that a base is required to reverse an acidosis.

The concern is that side effects of bicarbonate (namely intracellular worsening of acidosis) outweigh the potential benefits in acidemia.

Why is This Study Important?

Looked not only at important outcomes like mortality and hospitalization, but also looked at physiolgical data like acidosis or ketosis resolution.

Purpose (PICO format)

Adult and pediatric patients with DKA treated with bicarb or no bicarb for emergent treatment; outcomes were mortality and hospitalization duration.


Multiple centers


Systematic search by two investigators identified 508 potentially relevant citations. Any disagreements were adjudicated by a third independent investigator.

Outcome Measures

Primary outcomes of length of hospitalization and mortality. Secondary outcomes of resolution of acidosis, ketosis, potassium balance, tissue oxygenation, CSF acidosis, neurologic deterioration, and hemodynamic parameters.

Inclusion Criteria

Adult and pediatric patients with DKA and treated with bicarbonate were reviewed for inclusion

Exclusion Criteria

No review articles

No commentaries/letters/editorials

Articles not related to cerebral edema, bicarb, or acid/base in DKA


Of the 508 potentially relevant articles, 44 were selected and reviewed. There was only one double-blinded RCT and two nonblinded RCTs; the majority of studies were case-controlled studies.

No apparent impact on LOS; also, no published study in bicarb in DKA was able to comment on mortality–though, most studies excluded the severely ill DKA (i.e. severe metabolic acidemia).

The studies that seemed to see physiological benefit in RCTs found improved pH and bicarb levels at 2h; however, 24h later, there was no difference.

Paradoxical worsening of ketonemia; specifically, slower decline in the ketonemia in the first hour of bicarbonate infusion.

Variable results on the potassium or rate of decline in blood lactate. Furthermore, there was a variable, non-statistically significant difference in CSF pH and bicarb levels within 24 hours in bicarb and control groups.

A small number of the analyzed studies included outcomes like neurologic performance or hemodynamics but found no significant differences.


Most of the studies included in this systematic review excluded critically ill/severe metabolic acidemia DKA cases. The pH threshold for bicarbonate administration varied between < 7.00 to < 7.20. Dosages varied with more recent dosing strategies 120-150 mmol for adults. More recent studies were preferentially using slow infusions of half-isotonic or isotonic preparations (approx 1%) or small intermittent boluses.

Conclusions of the Authors of the Study

Data heterogenous and without clear signal for benefit in bicarbonate administration for DKA; potential for worsening ketonemia and requirements for potassium. However, there could be a transient improvement in acidosis without clinical outcome changes.

Take Home Points for Us

The potential for worsening ketonemia and potassium requirements seems minor; furthermore, bicarb’s transient improvement in acidosis bears no clinically relevant outcome. The minor, transient improvement in pH could be useful in severe acidemia as a brief temporizing measure in rare situations but remains unproven.