Do Prehospital Antibiotics Matter?

In short, probably not, but still not completely disproven.

This randomised controlled open-label trial looked at giving 2 grams of IV ceftriaxone to patients that met SIRS criteria (save for WBC- testing unavailable to EMS) with suspected infectious illness. Patients were randomly assigned (1:1) to the intervention group or usual care group using block-randomisation with blocks of 4. This study took place across ten large regional ambulance services serving 34 secondary and tertiary care hospitals in the Netherlands over a 2 year period. They screened 3228 patients of which 2698 were eligible (pregnancy, beta-lactam or ceftriaxone allergy, suspected prosthetic joint infection, among others); 1150 in the usual care arm (IV fluids, supplemental oxygen prn), and 1548 in the intervention group (2g ceftriaxone plus usual care). 13 patients in each arm were excluded from final analysis or excluded due to withdrawn consent or being lost to follow up. The primary outcome was all-cause mortality at 28 days.

So, while they screened over 3,000 patients over 2 years (a massive undertaking!), unfortunately, only 37 (3.3%) patients in usual care and 66 (4.3%) patients in the early antibiotics group had septic shock. Perhaps you could make an argument that the intervention group was slightly sicker with 22% vs 17% having 2 or more qSOFA criteria. Despite a median time to antibiotics of 70 minutes in the ED (thus, probably close to 90+minutes faster in the intervention cohort), and with 14% having antibiotics >3hrs from presentation and 14% having none at all (suspected viral syndrome) – there was 8% mortality in both arms at 28 days and 12% at 90 days in both arms. No difference.

When you look at mortality for septic shock it was 27% (10/37) in the prehospital antibiotic cohort vs 28.8% (19/66). Again, not statistically significant. While prehospital antibiotics might make a difference in a larger cohort, its probably going to be very hard to ever do that study – this was a 2 year study looking at over 3,000 patients and they were barely able to accumulate over 100 septic shock patients.

While an American might argue “they only gave ceftriaxone, you need a real drug like Pip-tazo and vancomycin!” – slow down. The authors acknowledge that ceftriaxone may not have been appropriate because it was “a big gun” that they could all agree on and most patients were rapidly narrowed to receive, most commonly, amoxicillin–clavulanic acid with ciprofloxacin and ceftriaxone the second and third most common antibiotics given. They did not have culture reports back at time of publication, but having low mortality, and 9% of each cohort were not given antibiotics from the ED due to suspected viral illness makes me suspect that they do not have nearly the resistance problem (or concerns) that the Americans do, likely do to appropriate stewardship. Likewise, while one may be concerned about missed diagnosis due to premature closure, there was a miss rate of 1.4% in the intervention group vs 1.7% in the usual care group, also not statistically significant.

In the end, the authors provide a sensical view of the current state of prehospital antibiotics, “Studies showing that early antibiotic treatment is beneficial for reducing mortality found this positive association mainly in patients with more severe illness and a (time to antibiotic) of more than 5–6 hours… However, we currently do not advise antibiotic administration in the ambulance to patients with suspected sepsis.“

While it is certainly plausible that prehospital antibiotics may be beneficial for those with septic shock, it is a near certainty that, at least in the USA, sepsis hysteria would further ensue and the inertia of giving everyone a dose of broad spectrum antibiotics will likely occur – not to mention our continued fixation with iatrogenic salt-water drowning. The cost to the system – including other patients in the department – of responding to these prehospital alerts for those not in shock will likely be the hidden cost infrequently published or discussed by administrations.

Improving Outcomes, Improving Throughput, Radiology

Parting the SEA with the almighty H&P (& rapid MRI).

Necessity is the mother of invention, and sometimes, necessity comes in the form of hospital administration after a bad outcome. The authors of this paper, essentially developed a rapid MRI protocol for suspected spinal epidural abscess after “several cases of SEA associated with delayed diagnoses and poor outcomes prompted the chairs of the departments of emergency medicine, neurosciences, medicine, and radiology, and members of the Division of Healthcare Quality, to develop a multidisciplinary, clinical decision support tool and imaging protocol with the goal of facilitating early recognition of SEA.”

Wow. Talk about moving mountains. If you’re department is anything like mine, it takes hours to agree on where we’re getting take out from; I cant imagine adding in 4 entire departments into the lunch-ordering mix, let alone all agree on a protocol.

They took a relatively simple approach – if you have new or worsening back/neck pain AND a history of spinal abscess or current/recent (6 months) bacteremia, straight to MRI. I think the recent bacteremia often gets lost in the work up, so I appreciate that they put this front and center. If there is no recent spinal infection or recent/current bacteremia, They looked at risk factors- and I’ll make this simple and break it into 2 categories: people putting things where they dont belong (IVDA, vascular catheters, spinal procedures/injections) and the recurrently ill: ED visit or antimicrobial treatment within 30 days or an infectious process elsewhere. If yes, head to MRI.

I’m torn a bit on this- while I want to applaud the authors for not dwelling on a variety of risk factors that only a small portion of the population has – alcoholism, HIV, severe COPD, the undomiciled, HepC, oncology patients, transplant patients, etc; to say that this group is pretty much captured in the recent ED visit category probably misses a fair amount of patients on the first go-round. And here is the problem of trying to find a needle in the haystack – its hard to increase sensitivity and specificity without causing a delay at some other portion of the food chain – every stat MRI for so many additional back pain patients pushes out another patient and potentially extends at least 1 other patients length of stay.


Despite an increase from 56 MRI’s in the 7 months pre-intervention to 147 in the 7 months post-intervention, yield for a positive MRI (defined solely as SEA and not vertebral osteomyelitis or infectious discitis), went from 16.1% to 17.7%.

On first glance, that’s not a lot of improvement in yield, but they screened 3 times as many patients without losing yield! This is rather impressive. However, they tripled their ED MRI rate, and, even though they drastically cut turn around times from 8.6 hours to 4.4 hours from time of MRI order to radiology report, thats still well over 4 hours for patients with back pain in a highly optimized system. And while yes, they missed fewer SEAs, they probably still have a good percentage that they missed on first visit – the various forms of immunocompromised – the severe COPDer on repeated steroid prescriptions, the HepC patient, the elderly – these are likely missed on the first go round.

I think this is a great step towards creating a policy towards SEA workup. It needs some refinement, but is the best I’ve seen yet. It poses some issues for smaller facilities that do not have 24/7 MRI capabilities, as well as for consultants (neurology essentially becoming a house officer for ID and neurosurgery), and poses a big time crunch for the ED (again, neurology took control of these cases once the decision to MRI was performed, which the hospitalists must be thankful for!). In the end, there is no such thing as zero miss, but Baystate, with this study, demonstrates that, at least for one day, the H&P is not dead.

Critical Care, Mythbusting

Even Pharma is getting in on Vanco-PipTazo AKI

This was an entertaining 9 page meta-analysis espousing the therapeutic harm of vancomycin and pip-tazo in the form of acute kidney injury.  With a conflict of interest page that reads like a pharmaceutical mutual fund (The Medicines Company, Cubist, Pfizer, Merck, Forest/Allergan, Melinta), it’s no wonder that they infer increased mortality due to AKI, yet conveniently COMPLETELY ignore that the same papers they reference show no mortality difference – and if anything a trend towards mortality benefit for vanco-PipTazo.  Likewise, with dialysis rates <2%, the induced kidney injury is less likely to cause harm than a suboptimal drug that wont kill your bug.

They also fail to mention cefepime neurotoxicity.

There are other ways to go about this. Like, say, reviewing the damn cultures.

But in the end, since The Medicines Company and Melinta have new broad spectrum antibiotics on the market or on the way, it probably behooves them to run a slight smear campaign on current treatment regimens. Therefore, forgive me for considering the possibility that the authors intentions may not be pure.

Improving Outcomes

Review the damn cultures.

This is a multi-center observational cohort study performed over 5 years at two hospital systems. They reviewed over 1800 cases of gram negative bacteremia. About 20% of patients with a prior gram negative bacteremia (within the year) received antibiotics to which their prior cultures were resistant.

This is embarrassing. Just review the prior damn cultures. The answer isnt VancoPime reflexively for everyone. Hell, add on a dose of gentamicin, or whatever the prior cultures are sensitive to. Just write a note in the chart and explain it to the oncoming team.

Side note: bout 25% of admits within the last 90 days were resistant to ceftriaxone and cipro, with an 80% or better percentage for resistance (for ceftriaxone, ceftazidime, meropenem, cipro, or gentamicin – 61% for pip-tazo) to the same antibiotic if the same organism was isolated.

Regardless, blaming the surviving sepsis guidelines or the federal government, or whoever is simply trying to pin your own laziness on someone else. It takes no fewer than 5 minutes – and probably closer to 30 seconds – to review prior cultures. In the critically ill, this is utterly and completely unacceptable.

Improving Outcomes, Mythbusting, Neurology

Early vs late meningitis diagnosis: capturing the needle in the haystack

Needle in the haystack, infectious pathway, take 6.

This is a retrospective study looking at early vs late diagnosis of bacterial meningitis from three hospitals in Denmark (one looking at data from 1998-2014; the other two from 2003-2014). To be eligible, patients had to be >15 years of age, and, obviously, had to be hospitalized with a clinical presentation consistent with possible community acquired meningitis (any combination of headache, neck stiffness, fever, altered mental status, petechiae) with no alternative diagnoses made during or after admission. Furthermore, all patients also had to have a proven bacterial etiology by either: positive CSF culture, positive blood culture and CSF with >10 wbcs, bacteria seen on CSF gram stain, or bacteria in CSF by PCR or antigen analysis.

So what is early and what is late diagnosis? They define “early diagnosis” as being recognized in the ED (1.3 hours to antibiotics median), and “late diagnosis” as, well, not diagnosed in the ED (ie, diagnosed on the wards- 13 hours to antibiotics median). Over roughly 15 years, they saw 358 cases of bacterial meningitis, (~8 cases per year per institute – seems a bit high? They do not mention total number of annual ED visits), with 32% being classified as diagnosed “late.” … so, probably 2-3 cases a year of “late” diagnosis – a true needle in the haystack.

Why the late diagnosis? They tended to be older (65 years of age vs 56), less likely presenting with headache (58% vs 82%), less likely with neck stiffness (36% vs 78%), less likely with fever (59% vs 78%), with the classic triage of AMS, fever, and neck stiffness was only present 20% of the time in the late diagnosis group vs 50% in the early diagnosis…. So, it wasn’t an easy catch.

Why does this matter?  Welp, with early antibiotics having a positive effect on mortality (18% vs 36%) as well as unfavourable outcome (which they do not actually define, 37% vs 66%, in favor of early antibiotics).  This is a HUGE difference in mortality and unfavourable outcomes if you do not catch it early!  … Then again, do we do more harm by giving 1-2g of ceftriaxone to everyone who is a bit altered?  Would the risk of cdiff then outweigh the 2-3 annual misses? I’m not so sure.  What about the recurrent headaches and repeat visits for post-LP headaches?

If you really want to tease out the data a bit, 53% of late diagnosis patients vs 26% or earlier diagnosis patients had a head CT before the LP. 72% of “late diagnosis” patients tentatively had a non-infectious etiology- so let’s explore some of the tentative diagnoses:

loss of consciousness (19 patients)

stroke (12 patients)

intracranial / subarachnoid hemorrhage (7 patients)

impaired mental status (6 patients)

headache (5 patients)

back pain (5 patients)

seizures (5 patients)

loss of vision (2 patients)

(among others)


What I’m seeing here is a a trend towards a neurologic issue (a CT scan, a diagnosis of syncope / seizures, AMS, etc) – which may indicate that the thought of meningitis (or even endocarditis) may not have been entertained. Cant make the diagnosis if you dont think about it. In a similar vein, this diagnosis is rare and runs across a spectrum – on one end, the febrile, meningeal and altered, on the other, the vaguely unwell.  And that, surprisingly, even a 12 hour delay to antibiotics can wreck havoc on the patient.

The take home points?  Be vigilant, entertain the spectrum of disease for meningitis, but remember that every decision you make has consequences, including the decision to, and not to, perform an LP, not to mention the decision to indiscriminately give antibiotics for those “altered”.  Choose wisely, and remember there is no such thing as zero risk.

Critical Care, Improving Outcomes, Mythbusting

Procalcitonin: Holy Grail, or Holy Sh*t ?

Procalcitonin is marketed as, “a marker of broad routine use, both for differential diagnosis of bacterial infection as well as for antibiotic stewardship.

But is it?  This study looks at 107 ICUs that had >25 sepsis cases in 2012, and had an ability to perform procalcitonin (PCT) levels on their septic patients, and essentially looked to compare the outcomes of those that had PCT ordered and those that did not.  All in all, there were about 17,000 septic patients without a PCT ordered, and about 3800 patients with a slightly lighter wallet and slightly more anemic after their admission than their comparators.

There was little difference in baseline characteristics – save for those having PCT ordered more likely hailing from the West (27.9% of PCT orders vs 12.7% of those not getting PCT ordered) and the opposite holding true for the South (55.3% without vs 49% with PCT).  PCT was slightly less ordered at teaching facilities (37.8% of septic patients without PCT orders vs 31.9% of those with a PCT ordered).  All other OR were <1.25.

There was no difference in length of stay and no differences in mortality.

There was an increase in days of antibiotic treatment for those in whom a PCT was ordered (relative risk increase 1.17), and with that an accompanying increase in Cdiff (OR 1.42) .  Of course, 1 PCT begets another (33% of the time, and about 3 days later).  Patients with serial PCT orders had higher rates of antibiotic use, higher Cdiff, and again, no mortality benefit.

Stop the madness.  Indiscriminately ordering tests that will not change management should not be done.  And they certainly should not be repeated.

Critical Care

Who ya gonna call? #VancZosyn!

If there’s some strange cough in your resus room,

Who you gonna call? Vanc-ZoSyn!
If something’s fevered… and it don’t look good,
Who you gonna call? Vanc-ZoSyn!

I ain’t afraid of no Staph.
I ain’t afraid of no Strep.

If high lactates are running through your EMR,
Who you gonna call? Vanc-ZoSyn!


There’s been some FOAM rumblings about Vanc/ZoSyn causing AKI, but this was the first time it has been compared directly head to head with Vancomycin-Cefepime. This was a retrospective matched cohort study with 279 patients in each arm – one received combination therapy with vancomycin-cefepime (VC), the other received vancomycin-piptazobactam (VPT) for > 48 hours. Patients were excluded if their baseline serum creatinine was >1.2mg/dl or they were receiving RRT. Patients receiving VC were matched to patients receiving VPT based on severity of illness, ICU status, duration of combination therapy, vancomycin dose and number of concomitant nephrotoxins. The primary outcome was the incidence of RIFLE criteria-defined AKI, with a slew of secondary outcomes performed as well.

So, wait, what’s so special about RIFLE anyway? Glad you asked: In general, the worse the acute kidney injury, the higher the mortality.

Since this study shows an 11% AKI rate with VC and 29% AKI rate with VPT, maybe we can improve our mortality if we simply switch from zosyn to cefepime?

Except that this group reports mortality was actually worse in the VC group (though not statistically significant – 8.6% vs 5.7%). That’s right – the group with more AKI had less mortality. In other news, ICU stay was decreased (6 vs 8 days), which was statistically significant., and only ~1% of patients in both arms required long term hemodialysis.

While I was getting ready to click submit on this blog post, I found a second paper (published Nov 28, 2016) that looked at a matched cohort of 1633 VPT vs 578 VC patients, with essentially similar results – 21.4% AKI in VPT vs 12.5% VC.  This second paper found similar LoS, but also a similar trend in mortality-  6.9% for the VPT arm and 9.2 for VC.

So… I’m not certain what to make of this – but it seems more than fair to question whether drug induced AKI is a meaningful surrogate marker for sepsis mortality.  We need a long term look at mortality between VC vs VPT to see if VPT induced AKI follows the same trends. Maybe we’re trading a slight bump short term mortality for improved long term mortality with VC (or maybe not).  In the meantime, I think we need to pump the brakes on shouting about Vanc/Zosyn AKI until we sort this out a bit more.