Paul E. Sax, MD is the Editor-in-Chief, Journal Watch HIV/AIDS Clinical Care, Clinical Director of the Division of Infectious Diseases at Brigham and Women's Hospital, and Professor of Medicine at Harvard Medical School.
Here’s a little secret about those brilliant ID consults we do on patients with mysterious fevers:
Sometimes we don’t know what’s going on either.
I know, I know — shocking.
But now that the secret is out, I can tell you something we do know, and that’s how to recommend lots of tests — the more obscure, the better. Including a particular favorite, isolator blood cultures. If you do inpatient medicine, chances are you’ve had an ID consultant recommend these and may even have ordered them without knowing precisely what they are, or more importantly, or how they differ from the regular blood cultures.
So here’s the story on isolator blood cultures — “isolators” for short — almost in plain English:
Blood is collected in a sterile fashion.
Instead of going into regular blood culture bottles, the blood is put into special tubes containing a chemical that lyses (explodes) both red and white blood cells, “releasing” intracellular organisms.
In the micro lab, the tubes are centrifuged to concentrate any bugs that might be present.
The sediment is aspirated and placed on appropriate culture media — e.g., fungal media for “fungal isolators” and mycobacterial media for “mycobacterial isolators.”
Wait. Potentially for a very long time (weeks).
These cultures are also known as “lysis-centrifugation” cultures, which is more descriptive than “isolators” but harder to say.
So when should you order them? There is a literature about the superiority of isolators over standard blood cultures, but these comparisons are mostly outdated — for example, with advances in blood culture technology (see video below), candida grows just fine in regular blood cultures today.
Furthermore, even though isolators may be superior to standard blood cultures for certain rare infections (e.g., histoplasmosis, bartonella, blastomycosis), in most (all?) of these conditions, use of antigen, serology, or PCR testing has supplanted culture methods entirely.
So that leaves one proven and one possible remaining indication for isolator blood cultures:
Proven: Diagnosis of disseminated mycobacterial infection (in particular, M. avium complex) in a patient with advanced AIDS or other severe immunodeficiency. Regular blood cultures are pretty much useless here.
Possible: Diagnosis of some bizarre, fastidious pathogen (e..g., Malassezia furfur) in a patient with culture-negative endocarditis or a vascular line-related infection.
Which means that most of the time, when your ID consultants recommend isolator blood cultures, you can ignore them.
And show them this video by a Dr. Kimmitt, who certainly knows her stuff but clearly is in no joking mood:
Guaranteed: Every day at a hospital near you, a patient is receiving antibiotic therapy for an infection, and the orders include the following:
A slew of various oral medications, both continued from outpatient care and started anew on admission.
An intravenous antibiotic.
The odd thing about this combination is that there are many antibiotics with excellent oral absorption, so the IV antibiotic may be unnecessary. Provided that the patient is able to take pills and is eating, lots of antimicrobials can be safely and less-expensively given in their oral form.
Even worse, someone may be discharged from the hospital on intravenous antibiotics — risking all the problems of parenteral access (clots, infection, pain, and myriad catheter malfunctions which only happen in the middle of the night/weekends) — when there are multiple oral options that will do the job just as well.
As a result, all ID doctors have encoded deep in their genome a list of antibiotics that can be given orally in place of their IV counterparts, or even more importantly, substituted for something IV on discharge.
Here’s the list, with a miscellaneous comment or two:
Trimethoprim-sulfamethoxazole: 1) A double-strength tablet is gigantic, but it also comes in liquid form for the pill-averse; 2) I always ask our ID fellows to tell me precisely (individual drugs and dose) what’s in a double-strength tablet of “Bactrim”, and about half of them know. Do you?
Metronidazole: 1) I am amazed that after decades of use of this drug, there is still no significant resistance among Bacteroides spp. 2) A ID colleague of mine, who is married to a gastroenterologist, named her bird “Flagyl.” How perfect is that??!!!
Clindamycin: What a wonderful drug this would be — effective for a whole range of things – if it weren’t for that nasty C diff problem.
Doxycycline: We’re heading into the “doxycycline deficiency” season here in New England. Start those tick checks!
Rifampin: You can pretty much guarantee that if a patient needs intravenous rifampin, he/she also needs an ID consult.
Linezolid: 1) This is the only oxazolidinone antibiotic; 2) I don’t know what “oxazolidinone” means, nor how to pronounce it; 3) I do know that this is by far the most expensive oral antibiotic out there. Wow!
Fluconazole: We take it for granted today, but the leap from ketoconazole to fluconazole when it first came out was truly gigantic. Sometimes newer really is better.
What’s missing? Most importantly, the entire class of beta-lactam and beta-lactam-like antibiotics — there isn’t a penicillin or cephalosporin that achieves high blood levels with oral administration (amoxicillin and cefadroxil the closest thing), and if there’s an oral carbapenem out there, someone has been hiding it from me.
Finally, as I went through this list on rounds, the residents and medical students were trying to come up with some sort of mnemonic, but were stymied since all the drugs start with consonants. Any suggestions? And did I miss anything?
Gastroenterologists, ID doctors, C diff-sufferers, and microbiome-obsessed humanoids everywhere were treated to this surprising news recently — a decision by the FDA about fecal microbiota transplantation (FMT). From an email sent by the IDSA:
Because fecal microbiota transplantation (FMT) is not approved for any therapeutic purposes, an investigational new drug (IND) application is needed for the use of FMT to treat any disease including C. difficile infection.
More information is on the American Gastroenterological Association site here. This FDA decision was confirmed at a public workshop May 2-3 — “sold out” I’ve been told by one attendee — a meeting which included many interested clinicians and researchers. The FDA plans to hold internal discussions to further refine the regulatory issues surrounding FMT.
I certainly understand the perspective of the FDA, which must consider patient safety as its top priority. But the immediate practical effect of this decision is that getting FMT to the patients who need it — those with recurrent C diff — will now be much more difficult.
And the FDA decision underscores a profound irony in regulatory protocols in our country. A person struggling with C diff can walk into any pharmacy, Whole Foods, Trader Joe’s, GNC, etc, and spend a small fortune on various probiotics, the efficacy of which is marginal at best.
Some very hard-working folks at the NIH, CDC, and IDSA have updated the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, which are available for review here.
As with the previous versions (the prior iteration is from 2009), the OI Guidelines are comprehensive, exhaustively referenced (184 references for TB alone!), and authoritative. Note that the PDF version weighs in at 416 pages, so I doubt many people will be printing this out and carrying it around in their white coats. Fortunately, for the first time these Guidelines are also available in their entirety on-line in an HTML version, which is undoubtedly how most will access them, and certainly make them easier to update.
After a quick review (no, I have not read all 416 pages quite yet), here are a few of the notable changes, plus a couple of miscellaneous comments:
There is broadened discussion of when to start HIV therapy in the setting of multiple OIs, in particular tuberculosis. This reflects publication of several pivotal clinical trials — here’s a nice discussion of three of them, to refresh your memory.
There are updates on treatment of hepatitis B and C; for the latter, strong consideration of deferring therapy is explicitly mentioned for patients with minimal disease given the rapid pace of drug development. This must be the preferred approach for most patients right now, for obvious reasons.
Diagnosis and management of IRIS — again, in particular for TB — is covered for each OI.
The structure of the Guidelines is now different, with pathogen-specific tables of recommended prevention and treatment options at the end of each OI section.
Following ACIPs lead, they endorse the three-vaccine approach to preventing pneumococcal disease — one 13-valent conjugated vaccine and two 23-valent polysaccharide vaccines separated by 5 years; we further discussed it in Journal Watch here.
Vaccination for HPV is recommended for men and women through age 26. Related: still no formal recommendation to do anal pap smears on either men or women.
What about the zoster vaccine? Despite this study (presented, not published) showing that vaccination is safe in HIV-infected patients, the Guidelines provide no formal endorsement, only saying it “is contraindicated in persons with CD4 cell counts <200.” (For what it’s worth, I give it to all my patients older than 60 with cd4 > 200.)
At the end of the document, there are several summary tables as well as this clear and useful figure with the recommended immunizations (click to enlarge):
So I do have a few small quibbles/queries, but they are minor. Namely:
How did they come up with the order of OIs? It seems to be more or less random. Here’s how it starts — PCP, toxo, cryptosporidia, microsporidia, TB, MAC, bacterial respiratory infections… What the? Undoubtedly there’s a rationale I’m not seeing.
If you click on the “Endemic Mycoses” link along the left of the HTML version, you get three endemic mycoses (histo, blasto, cocci), plus two that are not generally thought of geographically, cryptococcus and aspergillus.
Still not much love for beta glucan for PCP diagnosis. With the caveat that we’ve used the test now for years, which makes me far from impartial, it really is quite useful — an HIV+ patient with advanced disease, respiratory symptoms, and a beta glucan > 500 has PCP until proven otherwise.
Note that the panel responsible for these guidelines is inviting comment; just send an email to ContactUs@aidsinfo.nih.gov by May 21, 2013.
I’m sure if we ask nicely, they’ll let us know how they came up with the order for the OIs…
There it is, right in your daily paper, on your tablet or computer screen, or wherever you get your news today — a headline about a great medical breakthrough everyone’s been waiting for:
Scientists on brink of HIV cure
Researchers believe that there will be a breakthrough in finding a cure for HIV “within months”
Yes, I read this exact headline recently. Here’s the full article, published in the English newspaper the Daily Telegraph. It details how some Danish researchers have figured out a way for “the HIV virus to be stripped from human DNA and destroyed permanently by the immune system.”
Furthermore, they are “expecting results that will show that finding a mass-distributable and affordable cure to HIV is possible.”
By all means, go ahead and read the full piece; you’ve got 20 free reads on the Telegraph website. As a treat, there’s a colorful stock photo too, showing red blood cells floating through some blood vessels, along with a few HIV virions glowing bright green — it’s very Fantastic Voyage-esque, minus Raquel Welch in her scuba gear.
But return here for a moment, please. I’m going to recommend three simple steps to getting the most from this — and other medical breakthroughs — in the mainstream media.
Step 1: Be a skeptic. As exciting as curing HIV would be, and no matter how much you’d like this to happen, just think for a moment about the plausibility of this story. Are scientists really on the “brink” of curing HIV? If so, why is this only appearing in the U.K. Telegraph? Trust me, this brink-of-cure has not yet appeared in peer-reviewed medical journals or at scientific meetings. And wouldn’t you expect this kind of advance, if real, to show up everywhere in media land? Fire up that Google machine, and see what you can find about it elsewhere — lo, it’s the great following herd, all stampeding after that same U.K. Telegraph story. And importantly, here’s a New York Times piece on the very same general subject — HIV cure — and they don’t even mention these Danish researchers. Sure, the Times misses some stories, but it’s got some pretty impressive Health and Science sections — could they miss this, researchers ON THE BRINK OF CURING HIV, no less? I think not. So perhaps Mr. U.K. Telegraph Science Reporter is exaggerating a bit, for the sake of his story, of course.
Step 2: Don’t be a complete snob — give the story a chance. This is the other side of that same coin. Sure, it’s been a challenge curing HIV, but we’ve got that Berlin patient (now living in Las Vegas, by the way) — he’s cured. And the baby from Mississippi, he/she is cured (sort of). Plus, a whole army of smart HIV researchers actively tackling the problem as we speak. In fact, this very same approach cited by the Danish researchers — stimulating the HIV reservoir with an HDAC inhibitor — is a leading candidate for a viable cure strategy; it’s being looked at by many groups. Hey, why can’t Good Ol’ Ole Søgaard and his team be the first to succeed? The extra funding provided by the Danish government — 12 million Danish kroner! — is further evidence of the soundness of Professor Søgaard’s approach.
Step 3: After all that, land someplace between Steps 1 and 2. Take a deep breath. Read the full piece. Discard the fluff: Brink of cure; 12 million Danish kroner; expect a cure to be available in months; you can distribute it to millions; it’s affordable, too. Focus on the facts: Some Danish researchers have some funding to investigate a potentially promising HIV cure strategy; they are testing it in a small number of people; some European scientists may soon be collaborating; we have no actual results yet to report.
After these three steps, all these medical breakthroughs — on HIV, cancer, Alzheimer’s, weight loss, male-pattern baldness, you-name-it — make a lot more sense.
On Friday, the NIH announced that HVTN 505, a clinical trial of an HIV vaccine using an adenovirus vector, would be stopped based on a finding of futility by an independent DSMB.
The study had enrolled some 2500 high-risk gay men in the United States. Here are the three key findings leading to this action:
New infections in placebo arm: 30
New infections in active vaccine arm: 41
Among those who got infected, no effect of the vaccine in lowering HIV viral load compared with placebo
While the difference between the two is numerically but not statistically different, it’s clearly in the wrong direction.
Furthermore, it hearkens back to the results of the STEP study — another HIV vaccine trial using an adenovirus vector, Ad5 — that demonstrated an increased susceptibility to HIV infection among participants with pre-study immunity to adenovirus. Though HVTN 505 excluded those who had antibodies to Ad5, the results from HVTN 505 suggest that something else might be going on, something related to Ad5 and protective HIV immunity.
(Confession: I have no idea what that might be.)
As with all studies closed by DSMBs, the detailed data analysis starts in earnest now. And though this outcome is clearly disappointing, it will be fascinating to see what the full results show, and most importantly whether we can learn anything about a way forward in this challenging research area.
5:00 AM: Oops, slept late.
5:30 AM: Drive to hospital; not much traffic.
6:00 AM: Round on inpatients. They’re all doing great! Wonder why they’re not more talkative.
6:15 AM: Coffee, gossip with other surgeons.
7:00 AM: Get in scrubs, prepare for first case.
7:15 AM: First case. Remove this person’s esophageal tumor.
11:00 AM: That was fun! Another person saved.
11:15 AM: Next case — bronchoscopy/mediastinoscopy; darn, non-small-cell lung cancer. Cigarettes are bad.
1:00 PM: Time to get lunch.
1:10 PM: Finish grant proposal. Give feedback to army of office staff, nurses, and PAs, who work for us.
2:00 PM: Next case. Remove this person’s lung nodule.
4:00 PM: Granulomas on frozen section? Great, it’s not cancer! Call ID consult.
5:30 PM: Start new grant proposal
7:00 PM: Time to head home. I wonder what part of the chest I get to remove tomorrow?
Now I don’t really know what his day is like. He might as well be piloting a hovercraft in the Everglades, periodically pausing to shoot crocodiles — that’s about how close the ID doctors’ daily life is to this imagined Thoracic Surgery life.
But I was thinking about this the other day when I was talking to him during a neighborhood party, because he implied mystification about what we do. In fact, he quickly acknowledged he couldn’t do what we do in a million years. “You guys know everything,” he said.
(Thank you. I didn’t disabuse him of this view.)
And while we might not — okay, don’t — know everything, it’s true we get to see absolutely everything that’s going on in the hospital. It really is quite extraordinary how diverse the cases we ID doctors see. On rounds or during clinic recently, I saw or heard about individual patients with the following medical/surgical/social/miscellaneous histories:
Shot a raccoon.
Weight > 700 pounds. [Unable to verify exactly.]
Weight = 83 pounds.
Adult with complex congenital heart disease.
Six total joint replacements — of the same joint.
Just arrived here from Mali.
Has a cat, two dogs, two birds, a guinea pig, and a rabbit. [All completely unrelated to his ID problem, but interesting nonetheless.]
Retired New Orleans chef, now sells pickles from his van.
CD4 = 6.
CD4 = 660.
Reported vodka consumption: 1-2 liters/day. [They say always double what people report.]
Fever > 107 Fahrenheit.
Tattoos on her ears — just her ears.
Started smoking at age 11 in Venezuela.
80% surface area burn.
Speaks only Hmong.
Sells real estate on the Baja Peninsula, lives in Boston.
Each paper actually includes within them two studies. (For some reason, all the studies sound like 1950s science fiction magazines.) Typical of the frenetic pace of drug development for HCV, the trial designs are a byzantine mish-mash of study populations, strategies, and endpoints, which can make interpretation complex. As a result, here’s an attempt to summarize some key outcomes, with a focus on the bottom line — cure — making the not-so-bold leap that “sustained virologic response at 12 weeks” = “cure”.
One paper looked at treatment-naive patients with any HCV genotype, and included the NEUTRINO and FISSION studies. NEUTRINO was a single-arm treatment with peg IF, RBV and sofosbuvir for genotypes 1, 4, 5, and 6, and FISSION a randomized comparison between sofosbuvir and interferon (both with RBV) for genotypes 2 and 3:
NEUTRINO: Genotype 1, 12 weeks of peg IF + RBV + sofosbuvir: 89% cure
NEUTRINO: Genotype 4, 12 weeks of peg IF + RBV + sofosbuvir: 96% cure (Note: very few genotype 5 or 6 patients)
In the randomized comparison for the genotype 2/3 patients, response rates were similar between sofosbuvir for 12 weeks and interferon for 24 weeks (both with RBV); the sofosbuvir strategy was better tolerated. No resistance to sofosbuvir was detected in any patient.
The other paper — remember, also with two studies — looked only at patients with genotype 2 or 3 HCV, and in whom “peginterferon is not an option”. In one study (POSITRON), this could be for multiple reasons, such as prior adverse effects, concurrent medical conditions, or just refusing interferon; they were randomized to RBV + either sofosbuvir or placebo for 12 weeks. In the other study (FUSION), these were patients who did not respond to prior treatment with interferon, randomized this time to 12 or 16 weeks of RBV + sofosbuvir. Again, some cure rates (all genotype 2 or 3):
POSITRON: Interferon not an option, 12 weeks RBV + sofosbuvir: 78% cure
POSITRON: Interferon not an option, 12 weeks RBV + placebo: 0% cure (Note: must have included this for safety reasons, right?)
Patients with cirrhosis and/or genotype 3 didn’t do as well — extending the treatment to 16 weeks seemed to increase cure rates
No doubt these are terrific results, suggesting that sofosbuvir-based therapy will be both more effective and better tolerated than current standard of care. And also no doubt this week’s “Liver Congress” will have further interferon-sparing studies for HCV that could make these published studies seem out of date, even before the sofosbuvir is approved.
Nonetheless, as of right now — April 23, 2013, 2:43 PM EST — as an editorialist appropriately notes, it’s not quite time to say farewell to the “Interferonologists” among us who spend the bulk of HCV treatment time managing side effects.
The good news is that time is undoubtedly coming soon.
We are being consulted by surgeons who are finding within blast victims tissues from other humans. We have been offering post-exposure prophylaxis. Have you folks developed any policies re PEP for explosion victims?
Welcome your thoughts,
Needless to say, the bombing victims are currently facing far greater challenges than exposure to blood-borne pathogens. But it’s a very reasonable query and, as it turns out, there’s an existing guideline that addresses the issue, published in MMWR in 2008.
Entitled “Recommendations for Postexposure Interventions to Prevent Infection with Hepatitis B Virus, Hepatitis C Virus, or Human Immunodeficiency Virus, and Tetanus in Persons Wounded During Bombings and Other Mass-Casualty Events” — MMWR has a real knack for titles — it’s a valuable resource for a a very tricky clinical problem. It appropriately starts by stating that “Decisions regarding the administration of prophylaxis after a mass-casualty event are complex,” then goes on to make the the following recommendations:
So in general, post-exposure prophylaxis for HIV is not recommended after bombings or other mass casualty events.
Still, the fine print does say it might be recommended in certain situations. One could imagine blast injuries in very high prevalence settings (Sub-Saharan Africa, certain urban areas in the USA) meeting this threshold.
Remember also that these were published in 2008, and at that time one major factor in the decision to withhold PEP was the toxicity of the intervention, which was zidovudine/lamivudine plus lopinavr/ritonavir. Today, with TDF/FTC and raltegravir the new standard of care, PEP is far better tolerated. (See here for the excellent New York PEP guidelines.)
So the bottom line? In grisly settings such as the one described in the above email — tissue of other humans embedded into humans — giving PEP is certainly defensible, guidelines notwithstanding.
Two weeks, two companies, two press releases, two future HCV drugs that begin with “S”:
March 28, 2013: Janssen Research & Development announced that it has submitted a New Drug Application to the FDA seeking approval for simeprevir (TMC435), an investigational NS3/4A protease inhibitor, administered as a 150 mg capsule once daily with pegylated interferon and ribavirin for the treatment of genotype 1 chronic HCV in adult patients.
April 8, 2013: Gilead Sciences announced that it has submitted a New Drug Application to the FDA for approval of sofosbuvir, a once-daily oral nucleotide analogue for the treatment of chronic HCV infection. The data submitted in this NDA support the use of sofosbuvir and ribavirin as an all-oral therapy for patients with genotype 2 and 3 HCV infection, and for sofosbuvir in combination with ribavirin and pegylated interferon for treatment-naïve patients with genotype 1, 4, 5 and 6 HCV infection.
For several years now, all clinicians who see patients with hepatitis C have been promising them better treatments “soon”, with admittedly little precision about exactly what this “soon” actually means.
But with these filings, we have a pretty good idea. It will be less than a year — maybe much less. Why is that?
These two drugs have looked pretty great in clinical studies to date.
The bar to leap over to be substantially better than current standard -of-care treatment for HCV isn’t exactly high — a fact that could get at least one drug, if not both, priority review and even more rapid approval.
One of my patients has joked that I’ve been saying “in a few years” for availability of better HCV treatment options for at least “a few years” now — so my time is up.
Of course, stuff could happen that holds up the approvals. A toxicity could arise that hasn’t been reported previously, or a tricky drug-drug interaction could crop up. Or the sun could explode.
But if these things don’t happen, then for patients with HCV genotypes 2 and 3, a non-interferon option looks like it’s right around the corner — sofosbuvir and ribavirin. For those with genotypes 1 and 4, a shortened, more effective, and all-round improved interferon-based regimen will arrive at the same time — pegylated interferon/ribavirin plus either simeprevir or sofosbuvir.
And even better, how about an off-label combination of these two new drugs as in this clinical study – in which case the interferon can be dropped entirely, right?
Let the choir sing out when that happens, and enjoy a hearty celebratory brunch at the famous Cambridge deli pictured above in honor of the new regimen.