Thursday, November 20, 2014

something something antibiotics something something

It's been a crazy couple weeks out here on the edge of the prairie. Clinical service, grants, papers, holidays, Ebola?, the ESCMID-SHEA course in Phuket and SHEA2015 have swallowed up my fall. Get those SHEA abstracts ready folks - the deadline is fast approaching - January 16th.

In the middle of this chaos, the CDC's Get Smart About Antibiotics Week seemingly appeared out of nowhere and CDDEP investigators just published a very nice antibiotic use point prevalence study in 6 US hospitals in this month's Lancet ID to coincide with the 'Get Smart' Campaign. Nikolay Braykov and Dan Morgan led the study and Nikolay wrote up a nice post describing what they found, which I've excerpted below:

We undertook a chart review study at six institutions – two teaching centers, three community hospitals and one VA – looking at the indications for starting antimicrobials, the use of culture and radiology results and the patterns of modifying empiric therapy in the first five days of treatment. We found nearly two-thirds of inpatients were receiving antibiotics, with empiric starts dominated by combinations of vancomycin, piperacillin/tazobactam and fluoroquinolones. It is likely that a lot of those initial prescriptions were unnecessary, as 30% of patients lacked fever or abnormal white blood cell counts at the start.

Appropriate cultures (on or before start of therapy) were collected from 59% of patients, and although 60% came back negative, only 22% of all evaluated patients and had their antibiotics narrowed or stopped (Figure). More specifically, 22/59 (37%) of patients with negative urine culture and 11/22 (50%) of those with negative blood culture had antimicrobials stopped or narrowed. Of pneumonia patients with negative chest imaging that proportion was 12/50 (24%).

Narrowing or discontinuation (of antibiotic therapy) was more likely when cultures were collected at the start of therapy and no infection was noted on an initial radiological study. In turn, escalation was associated with multiple infection sites and a positive culture (see table below).
It seems like diagnostic uncertainty drives a lot of possibly unnecessary antibiotic use. These results underscore not only the need for rapid diagnostics, but also the importance of mechanisms to assure tests are ordered in time and their results are actually used to optimize therapy – goals attainable through better stewardship programs and physician education.

A great point made recently is that the government’s resistance action plans should include steps to incentivize and expand the training of more ID physicians. Although the threat of drug resistance gets more public attention each year, “getting smart” about antibiotics, including their timely withdrawal and adjustment, ultimately requires the buy-in of current and future prescribers. 

Tuesday, November 18, 2014

Band Aid 30 (West Africa 2014)

Band Aid, a charity group founded by Bob Geldof and Midge Ure in 1984, raised money to combat starvation in Ethiopia. The original song (despite controversial lyrics) led to the successful Live Aid concerts the following summer. With the current plight of Ebola in West Africa, they formed a new group to sing revised lyrics like "where a kiss of love can kill you and there's death in every tear" to help raise money to combat the epidemic. I would have written where a break in PPE protocol can kill you and, of course, epidemiologically speaking, there's not death in every tear. The song is available on iTunes and a CD will be released soon. And if you dislike the song or want to give more, you can head over to Oxfam, MSF,  MSF (USA), UNICEF, or the CDC Foundation.

Wanted: Ebola test with perfect negative predictive value at time zero

The tragic death of Dr. Martin Salia has triggered a spate of news articles about the limitations of Ebola diagnostic testing. According to news reports, Dr. Salia tested negative twice early in his symptomatic period, and was already quite ill by the time he tested positive.

The fact that the most sensitive Ebola virus diagnostic test (PCR applied to a blood sample) may not be positive until 3 days after symptom onset is well known, however. The reason for this has to do with the pathogenesis of Ebola virus infection. The point of entry and initial replication for Ebola is the “dendritic” cell. Present in large numbers in the skin, mucosa and intestinal lining, dendritic cells are sentinels, guarding the interface between the human immune system and a hostile environment. They encounter invaders, engulf them, and present their antigens to cells of the adaptive immune system. Dendritic cells carry the virus to lymph nodes and other organs of the “reticuloendothelial system” (liver, spleen). So before the virus reaches detectable levels in the blood, there may be hours-to-days of replication in these cells and organs, along with symptoms of fever and fatigue. A test, even a very sensitive test, that is applied to blood will not detect the virus until it appears in the bloodstream in larger numbers. 

This lack of a rapid and accurate diagnostic test early in the Ebola disease course is a major problem—not only for early initiation of therapy for those infected, but also for the management of “persons under investigation” (who may require Ebola-level isolation precautions for several days while awaiting a negative test that has been taken at least 3 days after symptom onset). 

But this problem plagues infectious diseases diagnostics generally. As this recent Lancet ID article points out, the lack of early and sensitive diagnostic testing is one reason why so many patients in our hospitals receive days of unnecessary antimicrobials. More on this study later, perhaps from Eli, one of the authors!

Monday, November 17, 2014

Why can't we easily clean our stethoscopes?

I just finished two weeks on the inpatient internal medicine service. When we round on the service every morning, I insist on 100% hand hygiene and 100% stethoscope hygiene but one of these targets is far easier to achieve than the other. As Mike mentioned last year, almost 50% of stethoscopes are contaminated with pathogens including S. aureus and MRSA. Despite this level of contamination, hospitals have done almost nothing to make cleaning them quick and easy. Like many (? all) hospitals, we have hand rub dispensers every few feet but nothing easily available to clean our stethoscopes. I usually end up "bothering" nurses to give us a few alcohol prep pads, but this uses up their daily supply and generally seems like an unnecessary barrier. Why can't we have wipes next to the hand rub dispensers outside of every room? That way we can actually achieve 100% stethoscope hygiene. If we don't develop good systems, we can't expect good results. How do you guys practice stethoscope hygiene at your hospital?

Monday, November 10, 2014

Getting to zero

By my count, there are now zero persons in the United States who are actively infected with Ebola virus.  This is the perfect time to donate your time or your money to Ebola response in West Africa.

Also, Kaci Hickox still doesn't have Ebola. She should be allowed to go bowling.

Finally, one observation about our weirdly, uniquely American response to Ebola virus. The CDC Guidance for Monitoring and Movement Restriction treats healthcare workers who have "direct contact while using appropriate personal protective equipment (PPE) with a person with Ebola" differently based upon whether they were caring for patients in countries with or without "widespread Ebola transmission". Thus brave volunteers returning from West Africa are under more stringent monitoring and movement restriction guidance than are those who might care for a patient in New York, Texas or Iowa. Yet if you compare the ratio of 'healthcare worker acquisitions/Ebola infected patients' in the US versus West Africa, I'm not sure there is any contest (2 acquisitions/9 Ebola patients = .22--what's 22% of 13,268, the total number of cases thus far in West Africa?).  This isn't an argument to be more restrictive about those who care for Ebola patients in the US, it's an argument to chill the #&*% out about humanitarian healthcare workers returning from the outbreak zone.

Monday, November 3, 2014

Sunday, November 2, 2014

Causal opacity

Medicine as a science is predicated on causality. We seek to understand the causes of disease. Similarly, in the field of patient safety, we aim to determine the causes of adverse outcomes: What factors led the nurse to administer the wrong dose of heparin to Mr. Smith? What caused the surgeon to operate on the wrong knee? Using root cause analysis, we can work backwards from the adverse event to determine the underlying causes. 

Now consider the case a of 24-year old man hospitalized for 3 months following multiple, life-threatening injuries following a motorcycle crash. He required 17 operative procedures, a 4-week ICU stay, and had numerous invasive devices (including central venous lines, endotracheal tube, urinary catheter, ventriculostomy catheter, arterial line, and external fixating devices). On hospital day 93, he develops MRSA bloodstream infection. The magic question is this: when was MRSA transmitted to this patient? And, of course, in cases such as this, we are never able to answer that question. The field of infection prevention is plagued by causal opacity—we are rarely, if ever, able to connect cause to outcome in non-epidemic healthcare associated infections.

In infection prevention, causal opacity is the result of two factors. First, the transmission event is silent since the pathogens are invisible to the eye. Second, the incubation period temporally separates cause from effect. With multidrug resistant organisms, the intermediate state of colonization, which can extend for very long periods of time, can separate transmission from onset of infection by months or even years.

Causal opacity also negatively impacts hand hygiene compliance. Imagine if you failed to wash your hands, examined a patient, and the infection in the patient manifested within seconds after touching the patient. Like an instantaneous electric shock, the immediate feedback would probably keep you from ever failing to wash your hands again. Recently, causal opacity has hampered our ability to understand why currently available personal protective equipment may be failing us in caring for patients with Ebola virus infection.

The end result is that causal opacity makes it harder to hold persons and systems accountable with regards to infection prevention. Yes, causal opacity sucks. But it’s an integral part of what we signed up for. Otherwise, we’d all be cardiologists or urologists—driving better cars, but bored silly.

Saturday, November 1, 2014

Ebola primer, v2.0

  • The current outbreak in Guinea, Liberia, and Sierra Leone is the largest ever recorded, with approximately 14,000 cases to date. Mortality rates in African treatment units exceed 60%.
  • The natural reservoir of the virus (a filovirus) is suspected to be fruit-eating bats.
  • Transmission occurs via contact with infected human body fluids (blood, saliva, sweat, vomitus, stool, semen, breast milk, and tears). Most transmission events are associated with direct contact with blood and body fluids. Transmission via indirect contact (i.e., fomites) can occur but appears to be uncommon.
  • Nosocomial transmission is a key driver of outbreaks. Healthcare workers are at high risk for infection.
  • Transmission has not been demonstrated from individuals who are in the asymptomatic incubation period. Even in the early stages of symptomatic disease, risk of transmission appears to be very low. As the disease progresses, infectivity increases. Infectivity is highly positively correlated with the patient's viral load.

  • The incubation period is 2-21 days (usually 5-7 days).
  • The illness is characterized by onset of fever, chills, myalgias and malaise. This is followed in a few days by GI symptoms (nausea, vomiting, profuse diarrhea and abdominal pain), and headache. GI fluid losses can be as high as 10 L/day. Relative bradycardia is common.
  • Hemorrhagic symptoms usually occur at the peak of illness and include maculopapular rash, petechiae, bruising, and bleeding from venipuncture sites. Gross bleeding from the GI and GU tracts is usually only seen in dying patients. Of note, overt bleeding has been uncommon in the current outbreak.
  • The late stage of disease is manifested by cytokine storm, multiple organ dysfunction syndrome, shock, capillary leak syndrome, seizures, delerium, coma, bleeding and anuria.
  • Laboratory findings include azotemia, leukopenia, thrombocytopenia, elevated transaminases, severe electrolyte abnormalities, proteinuria, and markers of DIC. Bilirubin is typically normal.
  • Spontaneous abortion occurs at high rates in pregnant women and mortality rates are higher in pregnant women.
  • Age is associated with mortality (highest survival rates are seen in those <21 years old).
  • Mean time from onset of symptoms to death in African treated cases is 10 days.
  • In survivors, the convalescent phase is long.
  • Ebola viral disease should be suspected in a patient with a history of travel to an outbreak area who has fever or other associated symptoms, though other infections (e.g., malaria, typhoid fever) must also be considered.

Diagnostic Testing 
  • Diagnostic testing focuses on PCR, which may be negative in the early stages of infection.
  • In the United States, most testing is currently performed in public health laboratories. 
  • A commercially available PCR assay (by Biofire Defense) with a 1 hour turn around time was given an Emergency Use Authorization by the FDA on 10/25/14.
  • Viral load in serum increases as the disease progresses and may be as high as 10 billion/mL at the time of death.
  • Viral load mirrors clinical response and when undetectable establishes that the patient is no longer infectious and can be released from isolation.
  • Viral load at the time of presentation predicts mortality (VL <100,000 associated with 33% mortality, whereas >10 million was associated with 94% mortality in data from Sierra Leone). 

  • Treatment is focused on aggressive supportive care, particularly fluid and electrolyte management. Antiemetics and antimotility agents should be used to reduce GI fluid losses. 
  • Hyperimmune serum from recovered patients has been used in the United States.
  • No approved antiviral therapy is currently available. 
  • Experimental therapies include brincidofovir (by Chimerix), monoclonal antibody (ZMapp by Mapp Biopharmacuetical), and TKM-Ebola (small interfering RNAs by Tekmira).
  • Corticosteroids, nonsteroidal anti-inflammatory drugs, and aspirin are contraindicated. 
  • Early treatment in developed countries appears to be effective.