During the past few weeks the case of a patient with MDR Klebsiella infection has made the news. We are told that this particular pathogen is “resistant to 26 antibiotics”. We were informed that the patient had multiple prior hospitalizations in India, supposedly the origin of the uncontrolled untreatable infection.
CDC released a bit more information in MMWR on Jan. 13, 2017. The organism, an NDM-positive, mcr-1 negative K. pneumoniae isolate was described as resistant to colistin and aminoglycosides, and intermediate susceptible to tigecycline. However, the authors then goes on to tell us that the Klebsiella strain was only susceptible to fosfomycin, a drug ”approved in the United States only as an oral treatment of uncomplicated cystitis; an intravenous formulation is available in other countries”[1].
The scenario is reminiscent of a case we described in an earlier blog which details how difficult it can be to import life-saving antibiotics into the USA. Even if these drugs are approved elsewhere just not in the USA.
We are informed by CDC that such pan-resistant strains are really rare and that it is important to obtain a travel history. Hey, and don’t forget contact precautions and isolation procedures, please!
The MMWR note says nothing about therapeutic options or how to obtain fosfomycin IV. How ironic, almost cynical, you may say.
This kind of advice reminds us of medical practice in the Middle Ages when doctors believed in the miasma theory of infection and therefore advised patients to leave populated areas and head for the countryside to avoid the plague. Those with the disease were left behind to die. Appropriate advice in times when there were no antibiotics, no doubt. Now we have CDC doing pretty much the same.
The ‘abysmal state of sanitation’ in rural India is hard to imagine: households have cellphones and TVs but do not have toilets [2] This is a set-up for disease transmission and a haven for bacterial recombination, made worse by a dismal public health record to ensure even the most basic hygienic standards
Frankly, we would have expected more practical advice from the CDC. Why not – as we proposed earlier – make fosfomycin IV more easily available from a European source? Or stockpile it under the aegis of CDC for quick retrieval? Here are some other thoughts / alternatives:
- Obtain fosfomycin on a compassionate use basis from Zavante Therapeutics, which is a US company working on a submission for fosfomycin IV (ZTI-01)?
- Use the veterinary formulation of the drug. Fosfomycin IV has been used for over 40 years in livestock [3], but the drug is not listed in the Green Book of Approved Veterinary Drugs issued by the FDA [4]. However, fosfomycin and all its formulations are approved in Canada [5] and, of course, south of the border.
- Obtain an experimental drug undergoing development. FDA, CDC or BARDA have susceptibility information on novel drugs in the pipeline, that is not yet in the public domain and could help in such a dire case.
Clearly, the K. pneumoniae strain was resistant to aminoglycosides but we have not heard whether plazomicin was tested as well, a drug now in Phase 3. How about eravacycline or omadacycline, some newer tetracyclines with better PK than tigecycline? There are other NCEs or combinations of drugs (see the Spero line-up) which could be considered in a desperate situation. - If all else fails, should one simply buy the drug from Sigma-Aldrich? Their laboratory-grade fosfomycin should be good enough [6], but talk to your institutional Ethics Committee first before you go this route. The lawyers are lurking.
None of this happened for the patient in the MMWR report – she was treated with vancomycin, Zosyn, Unasyn, aztreonam, ertapenem, meropenem, and polymyxin B, all drugs with documented ineffectiveness.
If Obama or Trump or Gates had an MDR infection like this, would exceptions be made and fosfomycin IV be flown in from the outside? You bet!
Churchill was treated with an ‘experimental’ sulfonamide when he came down with pneumonia in 1943.
We recognize that a severely infected sick patient cannot easily be transported from the US to another country which has a more liberal drug importation philosophy. Maybe patients with MDR infections should not return to the US and instead head for Canada, Europe or Mexico.
It is not enough for CDC to tells us to wash hands and not spread bad germs. Testing for the mcr-1 gene and informing us of its absence in that isolate is pure academics and in no way helps us manage these infections.
We need more flexible and innovative approaches. None of this was offered in the CDC notification which showed zero compassion. Very disappointing! Very bureaucratic! Very sad!
We need to become AIDS activists again and fight back against an inveterate system.
References:
[1] L Chen. Notes from the Field: Pan-Resistant New Delhi Metallo-Beta-Lactamase-Producing Klebsiella pneumoniae — Washoe County, Nevada, 2016. MMWR Morb Mortal Wkly Rep 2017;66:33.
[2] S Nayyar. https://www.healthissuesindia.com/2014/02/05/sanitation-health-hygiene-india/
[3] D Perez. Fosfomycin: Uses and potentialities in veterinary medicine. Open Veterinary Journal 2014; 4: 26
[4] http://www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/default.htm
[5] http://www.hc-sc.gc.ca/dhp-mps/prodpharma/pdl-ord/pdl_list_fin_ord-eng.php#a2
[6] http://www.sigmaaldrich.com/catalog/search?term=fosfomycin&interface=All&N=0&mode=match%20partialmax&lang=en®ion=JO&focus=product
[7] M Castanheira. Detection of mcr-1 among Escherichia coli Clinical Isolates Collected Worldwide as Part of the SENTRY Antimicrobial Surveillance Program in 2014 and 2015. AAC 2016; 60:5623
[8] WHO Critically important antimicrobials for human medicine – 4th rev. 2016; http://apps.who.int/iris/bitstream/10665/251715/1/9789241511469-eng.pdf?ua=1
