An ongoing dialogue on HIV/AIDS, infectious diseases,
August 27th, 2017
Who’s Most Likely to Leave an Out-of-Office Message While on Service?
Once upon a time, I used being on service as a convenient excuse for not writing very much — or certainly, not writing very much of importance — on this site.
The on-service time also allowed me to poke gentle fun at my colleagues, several of whom always turn on an “out-of-office” message when they attend on the inpatient ID consultation service.
I’m talking about this thing that responds instantly when you email them:
I am currently attending on the inpatient consult service. During this busy time, I may not be able to respond to email in a timely fashion. If you need to reach me urgently, please page me by calling xxx-xxx-xxxx, or leave a non-urgent message here and I will respond shortly.
Thank you,
Rudolph
Reminding me of this post, my friend Carlos Del Rio sent me this email earlier this year:
Going on service April 1st. Should I put my “Rudolph” message up?
I’d advised Carlos to check Emory’s Policies and Procedures — am sure it’s in there somewhere.
Now, having just completed a couple of weeks doing inpatient ID consults — and falling behind on emails — I thought it time to add a few additional observations about this practice:
- Who is most likely to do it? Let’s call people who do this “OOODS.” (Pronounced like the first syllable of “noodle,” and standing for “out-of-office during service” types.) My anecdotal impression is that OOODS are predominantly academic physicians, people who know patient care is important but don’t do it on a day-to-day basis. Hence they want to “clear the decks” of other pressing responsibilities. A minority might be full-time outpatient clinicians who only rarely do inpatient work.
- When not on service, they are generally very responsive to email. OOODS are often “inbox zero” types who wouldn’t think of allowing the sun to set on a critical research or administrative query. So when busy consult days happen, and the long hours on the wards make it impossible for them to keep up, they want to reassure their colleagues and friends that they haven’t suddenly decided to abandon academic medicine for more frivolous activities. Imagine the speculation!
“Hey, I emailed Dr. Smith 12 hours ago, and he hasn’t gotten back to me yet — that’s weird, he’s usually so quick to respond. Plus, no out-office-message.”
“Yes, that’s weird. But he’s a pretty big Phish Phan — maybe seeing all their summer concerts?”
- They’re generally pretty important. Many exceptions to this rule, but the academic rank and productivity of OOODS is impressive. One study found that the number of citations for papers published by OOODS was significantly higher than non-OOODS, even when controlling for total RVUs generated on the consult service. NIH grant dollars and the impact factor of their published papers were also significantly higher. If you don’t believe me, the published paper can be found here.
- One person who inspired the original post identified herself almost immediately. Shortly after I wrote it, I received this email:
Hey, I’m Rudolph aren’t I??? Is that a bad thing?
First, let the record show that this OOODS person who emailed me was only one of several people who sent me a similar query, as I adapted the sample out-of-office message from a bunch of different ones used by friends and colleagues.
Second, it is by no means a bad thing — it’s just a thing some people choose to do; others don’t (I don’t) — as evidenced by the fact that this particular OOODS person was most deservedly just appointed an extremely important leadership position.
Congratulations, Rochelle!
August 20th, 2017
Two Quick Thoughts Inspired by Inpatient ID Consults, and An Inspirational Baseball Poster
Mount Ararat, original source of daptomycin.
A couple of quick thoughts for those of us doing inpatient care these days:
Thought One: Is daptomycin now preferred over vancomycin in most clinical settings?
It’s taken a while, but we’re getting there — close to that Gladwelllian “tipping point”. Allow this recap of vancomycin’s problems:
- The growing recognition that higher drug levels — the levels we want — bring with them more side effects.
- The extraordinary hassle and imprecision of monitoring vancomycin levels.
- The enormous variability in dosing due to differences in clearance from patient-to-patient.
- The lengthy vancomycin infusion time (at least 60 minutes/dose) which, if you have a patient on every 8 hour dosing, means they are spending many of their waking hours receiving vancomycin.
If you add to these issues the substantial decrease in daptomycin’s cost since it went generic, it’s hard to justify using vancomycin over daptomycin for many non-pneumonia indications these days.
Daptomycin is far from perfect, but if it replaces vancomycin there will be few tears shed on its behalf — vancomycin isn’t such a great drug either. Beta lactams are preferred over both of them for susceptible organisms.
And for the next time there’s a lull in the conversation with your friends, here are some fun facts about daptomycin, including how it was discovered on Mount Ararat in Turkey.
Thought Two: Outpatient parenteral antimicrobial therapy (OPAT) should be avoided whenever possible.
Two recent studies highlight the hazards associated with sending patients out of the hospital with intravenous lines to complete antibiotic therapy:
- Out of 339 patients prospectively studied from two academic medical centers, 18% experienced a significant adverse drug event, most commonly during the first two weeks after discharge. Note that most retrospective analyses have even higher rates, probably because many are discharged without being in an organized OPAT program.
- In people who inject drugs — a particularly challenging patient population who increasingly have “indications” for OPAT — a whopping 61% failed their OPAT course.
Aside from the medical challenges of OPAT, there’s also the clinical service side — which is dismal. Since payers typically do not reimburse providers for monitoring OPAT, this gives us ID doctors two terrible choices — provide the service for free because it’s good for patients or, alternatively, refuse to do it and document (leverage) the suboptimal care to get institutional funding.
The former is an example of our being “too nice”; the latter just makes me uncomfortable, but is increasingly required.
Bottom line: we should strive to give oral over IV antibiotics at discharge for all patients, except when the data strongly support parenteral therapy. Oral treatment is safer, cheaper, and usually just as effective.
Finally, given the current political climate, isn’t this poster just awesome?
It’s a subway poster from 1950, published by the Institute for American Democracy.
And as a baseball-crazy ID doctor, of course I love it!
Save
August 13th, 2017
Dog-Related Infectious Diseases as an Excuse to Show Pictures of Dogs
For proof that we’re not like other human members of the planet, when ID doctors think of dogs, it sometimes brings to mind one or more of following associations:
- Gastroenteritis due to Campylobacter jejuni. No, there’s nothing cuter in the world than a puppy — but remember that these little critters are particularly predisposed to symptomatic (and asymptomatic) campylobacter infection, and, given our inability to resist picking up puppies and cuddling them, not surprisingly can be the source of human infection as well. Older dogs are less susceptible, so probably best to keep the puppies out of the elder care facilities.
- The wonderfully named bacterium Capnocytophaga canimorsus. This is a rare cause of sepsis after dog bites — in particular in people without spleens, those who consume too much alcohol, and the immunocompromised. A good trivia question for parties is to ask someone the bug’s original name, which was “DF-2”, standing for “Dysgonic fermenter.” Then ask them what “dysgonic” means. Then ask the difference between “DF-2” and “DF-1”. That will make you the life of the party. (For the record, I have no idea what “DF-1” is.)
Dogs are the “definitive host” of Echinococcus granulosus. This parasitic infection (which can cause nasty cystic lesions in the liver, lungs, and brain) is most common in people who raise sheep, which like humans act as intermediate hosts. But dogs are required to complete the life cycle, and they get infected when they eat discarded meat and internal organs from echinococcus-infected sheep. That might be yuck to us, but it’s no doubt yum to them. Here’s the CDC-approved life cycle diagram, if you don’t believe me.- Rabies. (Cue scary music here.) Even though there hasn’t been a human case of rabies linked to a dog bite sustained within the USA in decades, every ID doctor frequently receives calls about dog bites and the risk of rabies. That’s not surprising since 1) dog bites still account for over 90% of human cases world-wide; 2) rabies is nearly 100% fatal, and; 3) there are anti-vaccine crackpots who have spread their nonsense to their dogs. Couldn’t make this stuff up.
Of course that’s hardly the full list — there’s Dipylidium caninum (dog tapeworm), Ancylostoma caninum (dog hookworm), Microsporum canis (ringworm), Brucella canis (transmitted to humans when infected pregnant dogs have spontaneous abortions), and Ehrlichia canis (the cause of ehrlichiosis), just to list those that have the Latin root for dog in their name.
And we could on with several other infections that, in various settings, have been linked to dogs. A true potpourri of zoonoses! There’s giardiasis, Yersinia pestis (yes, that’s the plague), leptospirosis, Pasteurella multocida (though cats really deserve most of the blame for this one) — even MRSA!
Which brings me to the real reason for this post, which is to show three pictures of dogs that struck me as particularly fetching, infectious risks of owning these beasts notwithstanding. First, my friends just got an adorable puppy named Elijah — and here he is.
Second, and just so someone close to me won’t get jealous, here’s a recent picture of a very vigilant Louie, who has clearly spotted some danger in the distance (or maybe just a squirrel).
Third, I happen to work with Francisco Marty, who is not only a remarkable clinician and clinical researcher, but also one extraordinary photographer. And below is proof, entitled “DUMBO’s Dachshund!”
Woof!
August 6th, 2017
Have We Reached the End of HCV Drug Development?
Rabbit or duck?
Two new HCV regimens gained FDA approval recently, bringing us closer to the end of this extraordinary phase of drug development.
Think about it — has there ever been a more spectacularly rapid improvement in treatment of anything? If so, please let me know what that is. Remember, as recently as early 2013, highly toxic interferon-based therapy (with ribavirin and telaprevir or boceprevir) was still standard-of-care.
The recent approvals: Sofosbuvir-velpatasvir-voxilaprevir (Vosevi) on July 18, indicated for patients who have failed prior treatment with either sofosbuvir or an NS5A inhibitor. Twelve weeks of treatment (one pill daily) will cure 95–96% of patients, and pretreatment presence of NS5A, NS3, or NS5B resistance mutations does not reduce response. A month of sof-vel-vox — which will only be used as a salvage therapy — is priced at $24,900.
Then, glecaprevir-pibrentasvir (Mavyret) was approved on August 3rd. A pan-genotypic regimen that includes both an HCV protease inhibitor and an NS5A inhibitor, “G/P” is 3 pills daily, requiring only 8 weeks of therapy in treatment-naive individuals without cirrhosis. Clinical trial results show cure rates in the high 90s, with a low incidence of treatment-related adverse events requiring drug cessation.
Glecaprevir-pibrentasvir can also be used in patients with renal 
impairment (including dialysis), prior treatment failure of genotype 1 with either an NS5A inhibitor or PI (but not both), and in compensated cirrhosis. Treatment duration should be increased to 12 weeks in those with prior treatment or cirrhosis.
So where does that leave us in terms of “unmet needs” in HCV therapy?
Let’s review what we currently have:
- Nearly 100% of those who get treated are cured.
- Most regimens are one pill daily.
- Ribavirin is rarely required for treatment-naive patients.
- Side effects leading to drug discontinuation are exceedingly uncommon.
- Treatment duration is only 8–12 weeks.
- Drug interactions are mostly manageable; if not, HCV treatment is so short that temporary discontinuation of the conflicting drug is usually fine.
- Several pan-genotypic options are available.
- Certain therapies are also effective for treatment-experienced patients with resistance.
- Some regimens are safe and effective for those with moderate-severe renal disease — even hemodialysis.
From a medical perspective, this doesn’t leave out a whole lot, does it? Treatment of HCV is so easy there’s a strong push in some circles to move it to front-line providers in primary care — and of course outcomes in their hands are as good as with hepatologists and ID specialists.
Yes, cost of and access to HCV therapy remains an issue, especially in certain regions.
But things have vastly improved in this area too. With prices way down from the crazy days of early 2014 (when the non-FDA approved “sim-sof” regimen was > $100,000/cure), we should anticipate that more payers will stop medically unjustified policies such as fibrosis criteria, negative toxicology screens, and limiting prescribing of HCV therapy to specialists.
And market forces are doing something — note that the wholesale price of G/P is $13,200 per month, very close to the negotiated discounted price for LDV/SOF with the VA and certain state Medicaid programs.
Which brings me back to the title of this post — Have We Reached the End of HCV Drug Development?
If we’re not there yet, we’re certainly close.
Here’s a poll about where we should go with HCV research — please vote!
Save
July 30th, 2017
Really Rapid Review — Paris IAS 2017
Last week, the International AIDS Society meeting returned to Paris for the first time since 2003.
Yes, you and I are that old. Jeeze.
Here’s a Really Rapid Review® of some of the conference highlights, roughly ordered by “cure”, prevention, treatment, and complications.
As always, feel free to use the comments section for notable studies I might have missed — thank you!
- A child remains “in remission”, with an undetectable viral load for over 8 years after stopping treatment. This case — similar the “Mississippi baby” but with no relapse — has no detectable HIV RNA in blood, small amounts of detectable HIV DNA, no replication competent virus, and none of the HIV immune responses typically seen in HIV controllers. Treatment course was 40 weeks around two months after birth as part of a clinical trial. One of my colleagues says it’s the closest thing to a “cure” since Timothy Ray Brown, though for obvious reasons it’s always risky to use that word.
- What happens when HIV is treated extremely early after HIV acquisition? A man on PrEP was diagnosed with an HIV RNA of 220, 4th generation Ag/Ab negative, around 10 days after acquiring HIV. He was treated for 34 months with combination ART, which led to numerous negative reservoir assays, then stopped treatment — only to experience virologic rebound (same as original infecting virus) 225 days later. In summary, reservoir and viral diversity were reduced — but virus not eradicated.
- More evidence that undetectable on treatment means a person won’t transmit HIV. There were zero HIV transmissions in 343 serodiscordant MSM couples followed an average of 1.5 years — which included an estimated 12,000 acts of condomless anal intercourse.
- “On demand” pre-exposure prophylaxis (PrEP) worked in the IPERGAY study even in those with less frequent sex. The regimen was 2 pills of TDF/FTC before sex, then one each of the next two days (4 total). Strategy was protective even in those taking 15 or fewer pills/month.
- Cabotegravir with every 8 week dosing looks good for PrEP. Pharmacokinetics somewhat different in men vs women, but these results demonstrate levels likely to be protective with every 8 week dosing after a 4-week loading dose. Phase 3 comparative study vs. TDF/FTC ongoing.
- Weekly MK-8591 effective in animal model of PrEP. The drug, a “nucleoside reverse transcriptase translocation inhibitor” with a mechanism of action somewhat different from current NRTIs, is highly potent with a long half life. Study used rhesus macaques and SIV; none became infected after SIV challenge that infected untreated controls.
- New HIV diagnoses in MSM have declined slightly in the USA since 2008. The reduction is steepest among men aged 34-44 and in whites, while rates are increasing in younger men (13-34), and in Hispanics, younger blacks.
- Bictegravir/FTC/TAF non-inferior to dolutegravir/ABC/3TC in treatment-naive patients. 92.4% vs 93.0% < 50 at week 48. Significantly less nausea in BIC/FTC/TAF arm, but both regimens very well tolerated. No difference in bone outcomes. No resistance in either treatment arm.
- BIC/FTC/TAF non-inferior to DTG + FTC/TAF in treatment-naive patients. 89.4% vs 92.9% < 50 at week 48. Again, no emergent resistance in any of the few study subjects with treatment failure. This BIC/FTC/TAF regimen is under review by the FDA; if approved, it could be available early next year. (Disclosure: I was the presenting investigator.)
- Doravirine/TDF/3TC non-inferior to EFV/TDF/FTC. 84% vs 81% < 50 at week 48. DOR with significantly fewer CNS side effects, better lipids. 1.6% of DOR vs 3.3% of EFV subjects with resistance. Results of this and prior phase 3 DOR study suggest this NNRTI has the best efficacy, safety, and tolerability profile in this drug class.
- Single-arm study (n=120) of DTG + 3TC demonstrated 90% success (HIV RNA < 50) at week 24. Good news, it seemed to work well even in the 25% with baseline HIV RNA > 100K. Less good news, one study subject (in the < 100K group) developed 3TC and possibly integrase resistance (a K263K/R mixture). Contrast this with zero resistance in any of the triple-therapy studies of DTG. Phase 3 comparative studies of DTG + 3TC ongoing.
- 3TC was non-inferior to TDF/3TC when given with fixed-dose DRV/r. With the caveat that this is an interim analysis of a fully powered study, and used a 400 copy/mL threshold, the results are encouraging — and DRV/r + 3TC is a much more attractive regimen than the LPV/r + 3TC regimen used in GARDEL. Note the use of a non-FDA approved DRV/r coformulation (study done in Argentina). In the USA, this would presumably be DRV/c, can we extrapolate?
- Switching to a single-pill coformulation of DRV/c/FTC/TAF was non-inferior to continuing a boosted PI. If approved, this would be the first boosted PI single-tablet regimen. A treatment-naive study (compared to DRV/c, TDF/FTC) is also ongoing.
- With 2 NRTIs, DTG superior to LPV/r as 2nd-line therapy after failure of a 2-NRTI/NNRTI-based regimen. The results so favored the DTG strategy that the study’s Independent Data Monitoring Committee stopped the LPV/r arm (all subjects are now receiving DTG). Findings should have a huge impact on clinical practice — will DTG (not boosted PI) based regimens now be the standard of care for second-line therapy? Can we extrapolate to those currently virologically suppressed on boosted PIs + NRTIs due to NRTI resistance?
- In patients with advanced HIV disease, adding maraviroc to standard ART did not improve clinical outcome. This was a very well done trial, negative results notwithstanding. More studies in this challenging patient population needed!
- DTG + TDF/FTC is as safe as TDF/FTC/EFV in pregnancy. Reassuring analysis of nearly 845 DTG-treated and 4593 EFV-treated pregnancies in Botswana, as infant outcomes were similar. A randomized study of TAF/FTC + DTG in pregnancy is ongoing.
- Raltegravir also appears safe in pregnancy. Pending results of ongoing studies, raltegravir plus TDF/FTC is our current go-to regimen in pregnancy — where it is much better tolerated than boosted PIs.
- Every 4 week or every 8 week injectable cabotegravir plus rilpivirine maintains virologic suppression. No additional cases of virologic rebound occurred between weeks 48-96 (there was one in the q8 week arm initially). The every 8 week strategy was nearly superior to oral therapy. Fully powered phase 3 studies of CAB/RPV given q 4 weeks are ongoing.
- A single dose of MK-8591 suppresses HIV RNA for at least a week. A dose as low as 0.5 mg achieved this effect, demonstrating extraordinary potency. One patient (according to the presenter) had prolonged suppression even after stopping therapy (he/she was supposed to go on standard ART).
- In patients at high CV risk, a switch from boosted PIs to DTG maintains virologic suppression, improves CV risk profile. Eligible subjects had no prior treatment failures. Lipid benefits were particularly beneficial with the DTG switch, similar to what was seen in SPIRAL and SWITCHMRK, both of which involved switching from boosted PIs to raltegravir.
- Zoledronic acid improves bone mineral density more than switching off TDF. Of course in patients with low bone density, clinicians should probably employ both strategies given the increasing availability of TAF.
- Telomere length is worsened by smoking (especially) and viremia. I cite this study since this molecular observation so strongly correlates with anecdotal clinical experience — so many of the patients I follow with “accelerated aging” have an extensive smoking or viremia history. Or worse, both.
- Glecaprevir/pibrentasvir highly effective in HIV/HCV co-infected patients. Strategies tested were 8 weeks for no cirrhosis (n=137), 12 weeks for cirrhosis (n=14), with 150/151 cured. This “G/P” pan-genotypic regimen is likely to be FDA-approved soon, and can be used with any integrase or RPV-based HIV regimen.
- Large (n = 721) randomized clinical trial of cryptococcal meningitis in Africa finds 1 week of amphotericin + 5FC is the best strategy. Note that fluconazole + 5FC (an all-oral regimen) was nearly as good, underscoring the need to make 5FC more readily available in resource-limited settings, as amphotericin treatment is not always feasible.
- Use of adjunctive corticosteroids in PCP does not adversely influence subsequent CD4 recovery. I’ve always wondered about this! Now we know.
Now for a few non-scientific observations:
-
Paris Street; Rainy Day. Gustave Caillebotte, 1877. Art Institute of Chicago.
The weather was mostly, cool, cloudy, and intermittently wet. Regardless, Paris is among the most beautiful and lively cities in the world. (Not such an original opinion, I know.)
- A bike race visited Paris at the same time. Lots of excitement.
- What a weird conference center. Numerous escalators, winding hallways, and a disorienting layout made getting around tricky. At least the session halls for the slide sessions were very comfortable (though some over-crowded).
- Why can’t we have a subway system like that? The Paris Metro seems to get better all the time — fast, clean, reliable, inexpensive. I’m sure it’s not perfect, but is there a better urban rapid transit system in a large city anywhere else?
- Although per capita cigarette consumption is roughly the same in France and the USA, it sure doesn’t seem that way. I’ll anecdotally say that lots of professionals (even doctors, gasp) and other well-to-do people smoke in France — you don’t see that much in the USA anymore.
- Next year’s conference is in Amsterdam. July 23-27.
Speaking of bicycling around Paris …
[youtube https://www.youtube.com/watch?v=s8ErsO92Bfw]
Save
July 19th, 2017
Mystifying Cochrane Library Review on HCV Therapy Elicits Strong Response from IDSA
Last month, the Cochrane Review published a controversial paper on HCV therapy that left many ID doctors and hepatologists perplexed.
After reviewing 138 randomized clinical trials using directly acting, non-interferon based therapies, they came to the following conclusions:
- The use of sustained virologic response (“SVR”) — or “cure”, if you want to use plain English — as a valid endpoint for predicting clinical outcomes is questionable.
- There is currently insufficient evidence that treatment with DAA-based regimens improves clinical outcome.
- The studies reviewed were at high risk of bias, so tended to overestimate benefits and minimize harm.
- More randomized clinical trials are needed.
Anyone — clinician, researcher, or patient — who has experienced the miraculous advances in HCV therapy that started in 2014 could easily be scratching their heads at these conclusions.
The FDA might be surprised as well, since they have allowed SVR as an appropriate “surrogate” marker of the effectiveness of HCV therapy for some time.
Fortunately, we now have a focused, persuasive response by the IDSA, just published in Clinical Infectious Diseases.
I strongly encourage anyone who doubts the clinical benefits of curing HCV to read the full paper, but in essence the argument goes like this:
- The review was overly selective in the papers it included. Remember, many HCV trials could not include a control group since DAA therapies were so rapidly effective and well tolerated it would have been unethical. These non-controlled studies were not included in the review.
- HCV cure as an appropriate marker for treatment efficacy was established during the years of interferon-based therapy. Liver inflammation (as measured by biopsy or serial LFTs), fibrosis, portal hypertension, splenomegaly, even cirrhosis improved in those with SVR. And I would add that some surrogate markers are more intuitively obvious than others — and you can’t really get more obvious than curing the very infection that’s causing the disease. HCV RNA is not an obscure, indirect tumor marker (oncology), or a change in lipids (cardiology). It’s analogous to HIV RNA in HIV therapy, only better. And is there any plausible biologic reason why HCV cure with DAAs might be less effective in improving clinical outcomes than using interferon?
- The time horizon to see the full clinical benefit for HCV cure will take many years. We’ve only had these therapies widely available since 2015 — hardly enough time to see reductions in the incidence of long-term complications such as cirrhosis or hepatocellular carcinoma. Note that we’ve already seen benefits in HCV transmission from treatment in a clinical cohort of MSM from Europe.
- Despite this short time period of DAA availability, clinical benefits have already been observed with HCV cure. These include resolution of vasculitis, spontaneous remission of non-Hodgkin lymphoma, and — perhaps most remarkably — stabilization or improvement in those with the most advanced forms of HCV liver disease.
I will note that this isn’t the first time a “systematic review” of an Infectious Disease treatment under the Cochrane name ended up with a surprising conclusion.
Remember this one on HIV treatment with TDF/FTC/efavirenz? The one which stated there was insufficient evidence to support its use, despite numerous randomized clinical trials documenting its efficacy? And its widespread adoption in clinical guidelines?
It may be hard to find today, since it was later withdrawn.
Save
July 9th, 2017
Should You Answer Medical Questions from Clinicians You Don’t Know About Patients You’ve Never Seen?
This email popped into my inbox the other day from a person I’ve never met:
Hi Dr. Sax,
I do mostly hospital-based ID in Pennsylvania, and was consulted on a newly diagnosed HIV patient with CD4 10, viral load 210,000, and lymphoma. I started him on Truvada and dolutegravir, which is going well so far. Because he complained of blurred vision, he had an ophtho evaluation yesterday which showed CMV retinitis. My drug-interaction checker says I can’t use valganciclovir with either tenofovir or abacavir, and if I replace the Truvada with a boosted PI, it will interact with his chemotherapy. What should I do for his ART?
Thanks so much.
Marie
There are two issues with this email worth discussing.
The easy part first — the medical question. Here’s my response:
Hi Marie,
There is no significant interaction between ganciclovir and tenofovir alafenamide, and even the interaction with tenofovir DF is theoretical, not an absolute contraindication. No interaction with abacavir either, so not sure where you are getting your information! (Use this site, it’s awesome: www.hiv-druginteractions.org.) So switch the Truvada to Descovy (tenofovir alafenamide/emtricitabine), that’s all you need to do. Safer for kidneys and bones, too.
Regards,
Paul
The second item to cover is whether we should be answering questions like this at all. Remember, this is from a person I don’t know, asking about a patient I’ve never seen.
Though I obviously responded to the query, there are a few reasons not to answer questions from clinicians you’ve never met about patients you haven’t seen.
The medical information might not be correct, or complete enough, to make a good recommendation. If you make the wrong suggestion, or your recommendation is misquoted, there’s the potential for patient harm. Even worse: if your name is in the chart, there’s a medicolegal risk — especially if you review patient data sent to you. The risk may be small, but who wants to take that chance?
And if you ask an economist, they would say it definitely makes no sense to answer these questions — not only are you being paid nothing, but there’s little chance of downstream revenues, and it takes time away from other remunerative tasks and opportunities.
But economists can be short-sighted, and this is one of those times. Obviously I thought it was better to answer the question than to ignore it for a bunch of reasons.
- Answering helps the patient. Sometimes cliches are true: helping people remains the primary reason most of us went to medical school to begin with.
- Answering helps the clinician. When I see a difficult case of coccidioidomycosis, I of course call an expert in this tricky fungal infection; cases of cocci are rare in Boston. And I’m so grateful when John Galgiani responds, given his voluminous experience. Ditto various cases over the years involving rapidly growing mycobacteria (Richard Wallace), bartonella (Jane Koehler), toxoplasmosis (Jose Montoya), Mycobacterium avium complex (Chuck Daley, Gwen Huitt), cytomegalovirus (Richard Whitley), and many others. Thank you!
- It was a straightforward, focused question, presented clearly. I didn’t quote the whole email, which included numerous other details about the chemotherapy regimen, but those were thoughtfully placed at the bottom of the communication.
- The person asking was polite. No dreaded Red Exclamation Point indicating that this was of the utmost urgency. (Here’s a thought — let’s ban that particular means of communication.) No “Thanks in advance for your rapid reply.” (Ugh.)
- It’s flattering when someone asks you questions in your area of expertise. Gosh, Marie chose to ask me about her patient’s HIV therapy? When there are so many other people she could have asked? Hey, maybe I should be thanking her! (Of course she might have sent the same email to 20 others, but … who’s to know?)
The bottom line is that I think we should be helping out other clinicians when we can — it’s just the right thing to do.
Save
July 2nd, 2017
Delafloxacin, a New Quinolone, Is Approved for Skin Infections — But That’s Not Where It’s Really Needed
MRSA chasing ciprofloxacin, 1991. (Not drawn to scale.)
The history of the fluoroquinolone antibiotics can be divided into four eras, alternating good news and bad:
- Ciprofloxacin is approved — it covers everything, and is miraculous. We’re talking some tough customers here. Pseudomonas aeruginosa! Staphylococcus aureus! Neisseria gonorrhoeae! Plus, pretty much every gram negative causing urinary tract infections. There was no intravenous formulation initially, but that hardly mattered since it had great oral absorption. I remember as a resident seeing a patient with a polymicrobial diabetic foot infection in 1990 who was facing a long course of IV antibiotics — but instead went on ciprofloxacin orally at the suggestion of a brilliant ID consultant. As I said, miraculous.
- Resistance to quinolones emerges — and quickly. Staph aureus, especially MRSA, quickly became resistant to quinolones. Then Pseudomonas aeruginosa. Then a host of other gram negatives urinary pathogens. Then gonorrhea. Then enteric infections. Plus, we learned ciprofloxacin never should have been approved for treatment of pneumonia to begin with — whether it was problems with poor pneumococcal activity, or inadequate lung penetration, or both, it clearly was a bad respiratory tract drug. Oh well, it was fun while it lasted!
- Respiratory fluoroquinolones ride to the rescue. Levofloxacin, moxifloxacin, and especially trovafloxacin picked up many of the bugs that ciprofloxacin was missing. In case those weren’t enough options, there was sparfloxacin and grepafloxacin and gatifloxacin and gemifloxacin too. All had far greater gram positive coverage than ciprofloxacin, especially for streptococcal isolates. Moxifloxacin and trovafloxacin also covered anaerobes. Trovafloxacin was FDA approved for no fewer than 14 indications — a world record! And while many predicted inevitable pneumococcal resistance with the extraordinarily widespread use of these drugs, it never became that much of a problem. There was a rule on most medical services that every patient had to receive at least one dose of levofloxacin before discharge. (I made that up.)
- TOXICITY. All caps, italicized, and bolded, for a reason. Quinolones, it turns out, are not so safe after all. The FDA pulled trovafloxacin (hepatotoxicity), grepafloxacin (QT prolongation), sparfloxacin (photosensitivity), temafloxacin (hemolytic anemia and allergies) and gatifloxacin (hypoglycemia) from the market for safety concerns. The few surviving quinolones have the dreaded black box warning for serious adverse effects. This describes not only idiopathic tendon rupture, but also “disabling and potentially permanent serious side effects that … involve the tendons, muscles, joints, nerves, and central nervous system.” While in some patients these side effects are difficult to distinguish from the multitude of other causes of fatigue, poor concentration, and joint pain, there’s little doubt that quinolones are highly toxic to certain individuals. Potentially life-threatening QT prolongation and Clostridium difficile — two problems separate from the quinolone toxicity syndrome, but still serious — can be added to the mix. The toxicity profile is bad enough that the FDA advised, in 2016, to limit outpatient prescribing of quinolones to “those who do not have alternative treatment options,” a major action for this regulatory board.
Into this messy mix, and arguably against great odds, we now have a new fluoroquinolone — delafloxacin. It’s available in oral and intravenous formulations (both given twice daily), is FDA-approved for treatment of skin and soft-tissue infections (based on the results of this study), and most notably, has activity against both Pseudomonas aeruginosa and Staph aureus, including MRSA.
In vitro, its coverage also includes most coagulase negative staphylococci, enteric gram negative rods, respiratory pathogens, Neisseria gonorrhoeae, Bacteroides fragilis, and Mycobacterium tuberculosis.
Various reviews (here’s a good one) will cite the fact that unlike most quinolones, which are zwitterionic, delafloxacin is anionic, leading to increased accumulation in bacteria. That certainly sounds impressive, and a quinolone with reliable anti-pseudomonal and MRSA coverage currently does not exist.
However, coverage and biochemistry notwithstanding, we might wonder why we need another treatment for skin infections, especially with the toxicity profile of quinolones. Indeed, the FDA-approved medication guide for the drug goes to great lengths to warn people about potential side effects.
There are two answers to this mystery. First, it’s easier to get FDA-approval for treatment of skin and soft-tissue infections than it is for other indications. Cue up your favorite low hanging fruit analogy.
Second, the drug was given priority review by the FDA since it was designated as a Qualified Infectious Disease Product (QIDP) under the Generating Antibiotic Incentives Now (GAIN) Act of 2012. While this act encourages novel antibiotic drug development, these approvals can leave clinicians scratching their head about why the drug is available at all:
Oh joy. Another MRSA skin drug. Will wonders never cease. I've had to update my table. Can anyone spot the trend? pic.twitter.com/td4BPCFgAS
— Brad Spellberg (@BradSpellberg) June 28, 2017
Ever the optimist, I’m hopeful that now that delafloxacin is approved, we will eventually see studies documenting its efficacy in clinical settings of greater unmet need.
Based on this search, it looks like trials in community-acquired pneumonia (ho-hum) and gonorrhea (good) are in the works. (The gonorrhea study was stopped — see comment below.)
Here are a few more study ideas, with admittedly much tougher patient populations and study endpoints, but leveraging delafloxacin’s antibacterial spectrum, bactericidal activity, and excellent oral bioavailability:
- A randomized, phase 3 clinical trial comparing oral delafloxacin with intravenous vancomycin or daptomycin for Staph aureus bacteremia. Randomization would occur after clearance of blood cultures. Stratify based on MRSA vs MSSA.
- A randomized, phase 3 clinical trial comparing oral delafloxacin with intravenous therapy in treatment of spinal osteomyelitis due to susceptible organisms. Randomization after stable on IV therapy. Stratify based on risk factor (injection drug use vs other) and causative organism (MRSA vs other).
- A randomized, phase 3 clinical trial comparing oral delafloxacin with intravenous therapy in diabetic foot infections. Stratify based on whether the study subjects underwent surgical debridement.
- A randomized, phase 3 clinical trial comparing oral delafloxacin with intravenous ertapenem or cefepime for treatment of complicated urinary tract infections due to resistant gram-negative organisms. Stratify based on Pseudomonas aeruginosa vs other.
So that’s 4 tough areas of ID practice to start. But why stop there? How about looking at delafloxacin in studies of MDR tuberculosis? Or non-tuberculous mycobacteria? Many interesting possibilities.
Ready to enroll?
And though totally unrelated, this made me laugh:
[youtube https://www.youtube.com/watch?v=0nkgw-4VB0M]
June 18th, 2017
On Father’s Day, A Rumination on Families with Lots of Doctors
My father is a doctor.
So was my father’s father. And my father’s uncle. And my father’s cousin.
But that’s not all. My father’s brother was also a doctor — he loved being a doctor more than anyone on the planet, and attended neurology meetings long after he retired, right up until the time he died last year.
My father’s brother-in-law (i.e., his sister’s husband) — you guessed it, a doctor.
It gets even more ridiculous. I have two first cousins who are doctors, and three first cousins married to doctors.
And I, of course, am married to a doctor myself. Her brother? A doctor.
Having all of these MDs readily available has had quite an influence on family dynamics. At one of our gatherings, my brother — not a doctor, he’s in finance — told an elderly aunt the name of the bank he was working for at the time.
Hard of hearing, she responded, “What medical school?”
These gatherings, not surprisingly, can sometimes seem more like medical grand rounds than holiday celebrations. You almost expect someone at Thanksgiving Dinner to say, “May I have the first slide, please?”
The medical profession runs so strongly in my family that at times I suspect our various dogs are, in their own doggie world, the dog-equivalent of doctors. A bit nerdy, scholarly, caring for others.
So why is it that some families take to medicine so avidly? It certainly isn’t a universal phenomenon — I routinely ask residency and fellowship applicants if there are doctors in their family, and most of them say no.
You can try researching this question, but it’s a tricky thing to search. (I tried.)
Let’s keep it simple, and list the reasons why people become doctors to begin with:
- You help people. We never really need to ask the existential question, so why am I doing this job again?
- It’s interesting. Patients, colleagues, scientific discoveries, technical challenges, policy issues — medicine is endlessly fascinating. No good doctor feels he or she has mastered their field; learning all the time is fun.
- You have a steady income. No, doctor salaries won’t touch hedge fund managers or real estate developers, or approach the revenues you might get when you sell your high tech startup to Google. And you won’t be able to afford the premiere real estate in the Bay Area or Manhattan — but let’s face it, nobody’s poor here.
- It’s prestigious. People like doctors. We might not be as popular as we once were, but it sure beats the reputation of lawyers, or politicians, or the CEO of Uber.
- You can do a lot of different things as a doctor. Aside from my wife (pediatrician) and me (ID doc), included in my family collection of doctors is a psychiatrist, a maxillofacial surgeon, an emergency room doctor, a sleep specialist, an obstetrician-gynecologist, a general internist, a nephrologist, and a Professor of the History of Medicine. I can assure you none of them does the same thing in a typical work day — yet all are doctors.
If those are the reasons why people choose medicine as a career, it still doesn’t quite explain why some families — like mine — have so many doctors.
Maybe we just suffer from a lack of imagination.
Happy Father’s Day! And yes, Dad, going to medical school was the right decision after all.
June 10th, 2017
What’s Your Favorite Antibiotic? A Fantasy Draft
Over on the journal Open Forum Infectious Diseases (that’s “O-F-I-D”, not “Oh-FID”), the generous people from IDSA and Oxford University Press have allowed me to record a series of podcasts, interviewing various interesting people in the ID field.
This time, however, I strayed from the usual format and asked my colleague Rebeca Plank to join me in a “draft” of our 5 favorite antibiotics.
Which is emphatically not to imply that Rebeca isn’t interesting. On the contrary — she happens to have one of the most impressive pen collections in all of Eastern Massachusetts.
Still, you may wonder, why did we do this? Several reasons:
- We sensed a burning need for this this critical educational resource, which as you will see teaches fundamental truths about these important therapeutic tools.
- One of us wanted to honor the upcoming baseball draft (hint: Rebeca couldn’t care less about baseball).
- Someone gave me a USB microphone, and it was sitting around doing nothing for way too long.
In short, mostly we did it for fun.
Take a listen! And while you’re at it, two questions:
- What are your favorite antibiotics, and why?
- What should we draft next?
Hope you enjoy.
(H/T to Joe Posnanski and Michael Schur for the draft idea.)
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
Learn more about HIV and ID Observations.
NEJM Journal Watch — Recent Infectious Disease Articles- Could a Virus Cause Some Cases of Parkinson Disease?
- What's the Optimal Dosing of Linezolid for Rifampin-Resistant and Multidrug-Resistant TB?
- What to Do After Virologic Failure on First-Line Therapy with a Nonnucleoside Reverse Transcriptase Inhibitor?
- Another Flu Virus Crosses the Species Border
- Observations from ID and Beyond: Does the Fact That AI Is Brilliant at Writing “Learning Objectives” Prove They're Not Really Needed?