Tuesday, January 15, 2019

Emergence of MCR-1 gene mediated colistin resistance

A rare antibiotic-resistant bacterial infection has been found in a Laramie County resident receiving care at Cheyenne Regional Medical Center (CRMC), according to a statement earlier this year by the Wyoming Department of Health (WDH) . Recent testing showed the organism infecting the patient, an enterobacteriaceae, also included a rare antibiotic-resistant gene known as MCR-1. It does not appear the infection was acquired at the hospital.

The mcr-1 gene makes bacteria resistant to colistin, which is used for multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter including NDM-1 metallo-β-lactamase multidrug-resistant Enterobacteriaceae.

Colistin has been categorized as one of the few “Reserve Group Antibiotics” by the WHO in its “Model List of Essential Medicines Amended August 2017”. According to the WHO, Reserve Group antibiotics should be treated as “last resort” options that should be accessible, but whose use should be tailored to highly specific patients and settings, when all alternatives have failed (e.g., serious, life-threatening infections due to multi-drug resistant bacteria).

Besides colistin (polymyxin), other last-resort antibiotics included in the WHO list are: Aztreonam, 4th generation cephalosporins (cefepime), 5th generation cephalosporins (ceftaroline), oxazolidinones (linezolid), tigecycline and daptomycin.

Emergence of the first mcr-1 gene, which confers polymyxin resistance, was reported from China in 2015 (The Lancet Infectious Diseases, Published Nov. 18, 2015). As of November 2, the mcr-1 gene has been identified in human isolates in 19 states and in animal isolates in two states in the US, according to the CDC.

These reported cases highlight the dissemination of extensively drug-resistant and pan-drug-resistant Gram-negative bacteria, which have become a significant danger to public health.

This means that colistin resistance is spreading globally.

With no new antibiotics on the horizon, the situation may revert to a ‘pre-antibiotic era’ as the WHO has also warned, unless steps are taken urgently to check this public health danger.

The WHO says that “These medicines (reserve group antibiotics) could be protected and prioritized as key targets of national and international stewardship programs involving monitoring and utilization reporting, to preserve their effectiveness.”

Colistin is misused in the meat and poultry industry in India for its growth-promoting effect.

Reportedly, government agencies including the department of animal husbandry, dairying and fisheries, Food Safety and Standards Authority of India, ministry of agriculture and farmers’ welfare, ministry of health and family welfare and the drug controller general of India have examined the issue and recommended that colistin cannot be used (Live Mint, Dec. 4, 2018). This needs to be implemented with immediate effect. A colistin use policy needs to be formulated to promote its rational use and prevent emergence of antimicrobial resistance to this “last-resort” antibiotic.

It is only through a concerted and coordinated global action that this imminent public health danger can be thwarted.

Prescribing the right antibiotic, at the right dose, for the right duration and at the right time helps optimize patient care and fight antibiotic resistance.

Dr KK Aggarwal
Padma Shri Awardee
President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)
Group Editor-in-Chief IJCP Publications
President Heart Care Foundation of India
Past National President IMA

Low gluten food labels to be out with only 'gluten free' label to stay

A gluten-free diet is one that that does not contain the protein gluten. Gluten is found in grains such as wheat, barley and rye (sometimes in oats).Gluten causes inflammation in the small intestines of people with celiac disease. A gluten-free diet is required by patients with celiac disease (1% population) as it helps to control signs and symptoms and prevent complications.

Earlier in 2016, the FSSAI had notified the Food Safety and Standards (Food Products Standards and Food Additives) Second Amendment Regulations, 2016 relating to standards for gluten food and low gluten food. Correspondingly it made changes in Food Safety and Standards (Packaging and Labelling) Regulations, 2011 in packaging labels for gluten free and low gluten foods (rice, millets, ragi, oats, rye, barley, maize, wheat, pulses and legumes) specially processed to reduce gluten content to a level 20-100mg/kg.

Under these new regulations, FSSAI defined gluten-free food as food that consists of or is made of one or more ingredients containing rice, millets, ragi, pulses or legumes. A “gluten-free food” is one in which gluten levels are below 20 mg/kg. It also said that 

“A food which, by its nature, is suitable for use as part of a gluten free diet shall not be named as ‘special dietary’, “special dietetic” or any other equivalent term, however, such food may bear a statement on the label that ‘this food is by its nature gluten-free’.”

The Gluten-Free Food Labeling Final Rule issued by the US FDA in 2015 has defined "gluten-free" as meaning that the food either is inherently gluten free; or does not contain an ingredient that is:

·         a gluten-containing grain (e.g., spelt wheat);
·         derived from a gluten-containing grain that has not been processed to remove gluten (e.g., wheat flour); or
·         derived from a gluten-containing grain that has been processed to remove gluten (e.g., wheat starch), if the use of that ingredient results in the presence of 20 ppm or more gluten in the food. Also, any unavoidable presence of gluten in the food must be less than 20 ppm. That is the lowest level that can be consistently detected in foods using valid scientific analytical tools. Also, most people with celiac disease can tolerate foods with trace amounts of gluten without causing adverse health effects. 

Why didn’t FDA adopt zero ppm gluten rather than less than 20 ppm gluten as one of the criteria for a food labeled gluten-free?

FDA used an analytical methods-based approach to define the term gluten-free and adopted < 20 ppm gluten as one of the criteria for a food labeled gluten-free because the agency relies upon scientifically validated methods for enforcing its regulations. Analytical methods that are scientifically validated to reliably detect gluten at a level lower than 20 ppm are not currently available. In addition, some celiac disease researchers and some epidemiological evidence suggest that most individuals with celiac disease can tolerate variable trace amounts and concentrations of gluten in foods (including levels that are less than 20 ppm gluten) without causing adverse health effects. (https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Allergens/ucm362880.htm

As per the FSSAI draft Food Safety and Standards (Labelling and Display) Regulations, 2018: The term “Gluten Free” shall be printed in the immediate proximity of the name of the product in the case of products described in regulation 2.14 of the Food Safety and Standards (Food Products Standards and Food Additives) Regulations, 2011, namely ‘Gluten Free’.

The term “Low Gluten” shall be printed in the immediate proximity of the name of the product in the case of products described in regulation 2.15 of the Food Safety and Standards (Food Products Standards and Food Additives) Regulations, 2011, namely: “Low Gluten”. The label shall carry a ‘warning’ that ‘the food labeled as Low Gluten may pose a risk for those with celiac disease.

But now the FSSAI has decided to take “Low gluten” label out of the regulation as in celiac disease no amount of gluten is safe. 

HCFI Recommendations

·         The term “Low gluten foods” to be taken out of the label.
·         Gluten free should instead be labeled as zero gluten (since the public perception is that gluten-free means some amount of gluten is allowed).
·         Awareness should be created that ‘beer’ contains gluten and is harmful to gluten sensitive population. The harm reduction alternative is honey water wine, which has < 3% alcohol.
·         There should be options for gluten-free foods in airlines and trains.
·         In all parties, marriages and restaurants, there should be a provision for gluten free foods. Medical associations should pass a resolution to this effect on priority.
·         Non-celiac wheat sensitive persons (up to 10% of the population) should be offered wheat-free food options.
·         Wheat available in the market should also be labeled as high gluten wheat and low gluten wheat (both are harmful to celiac disease but low gluten wheat may have some solution for non-celiac wheat sensitive persons).

Dr KK Aggarwal
Padma Shri Awardee
President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)
Group Editor-in-Chief IJCP Publications
President Heart Care Foundation of India
Past National President IMA

Monday, January 14, 2019

Now an epilepsy smart watch to monitor seizures in children

Following on the heels of the approval granted to Apple Watch Series 4 for ECG screening, the US FDA has now given the green signal to another wearable mHealth device - the Embrace smart watch.

The Embrace smart watch has been approved to monitor seizure activity in children as young as age 6. Its use in adults had been approved last February.

The watch uses advanced machine learning technology to detect patterns in motion and physiological signals that may be associated with generalized tonic-clonic seizures. It then immediately alerts parents and/or the nominated caregivers, via text and phone messages, allowing them to quickly respond. It also provides sleep, rest, and physical activity analysis.

Its unique property is its use of electrodermal activity, a signal used by stress researchers to quantify physiological changes related to sympathetic nervous system activity, also known as the "fight or flight" response. 

Embrace was tested in an epilepsy monitoring unit among 141 epilepsy patients, including 80 pediatric patients ages 6 to 21 years. Overall, 53 of 54 generalized tonic-clonic seizures were detected by Embrace for an accuracy rate of 98% during the clinical testing.

As the first direct-to-consumer product, the ECG app on Apple Watch Series 4 helps people to take an ECG right from their wrist, whenever they experience symptoms such as rapid or missed heart beat and also share the data with their doctors. The irregular rhythm notification feature on Apple Watch can now also monitor heart rhythms in the background and send a notification if an irregular heart rhythm is detected on five rhythm checks over a minimum of 65 minutes

(Source: Medscape)

Dr KK Aggarwal
Padma Shri Awardee
President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)
Group Editor-in-Chief IJCP Publications
President Heart Care Foundation of India
Past National President IMA

The DNA Technology (Use and Application) Regulation Bill - 2019 passed by the Lok Sabha

“The DNA Technology (Use and Application) Regulation Bill - 2019” was passed by the lower house of the Parliament last week. The Bill has been formulated recognizing the need for regulation of the use and application of deoxyribonucleic acid (DNA) technology, for establishing identity of missing persons, victims, offenders, under trials and unknown deceased persons and strengthen the justice delivery system of the country. DNA evidence is considered the gold standard in crime investigations.

The Bill seeks to ensure that the DNA test results are reliable, and that the data remain protected from misuse or abuse in terms of the privacy rights of our citizens.

The key components of this Bill include:

  • Establishment of a DNA Regulatory Board: Among the various functions envisaged for the DNA Regulatory Board are included: advice the Central Government and the State Governments on all issues relating to establishing of DNA laboratories and DNA Data Banks and grant accreditation to laboratories and to suspend or revoke such accreditation.

  • The Board will also ensure that the information relating to DNA profiles, DNA samples and any records thereof, forwarded to, or in custody of, the National DNA Data Bank or the Regional DNA Data Bank or a DNA laboratory or any other person or authority under this Act, are secured and kept confidential

  • No laboratory shall undertake DNA testing, analysing or any other procedure to generate data and perform analysis relating thereto without obtaining accreditation from the Board.

  • Establishment of the National DNA Data Bank and Regional DNA Data Banks or every State, or two or more States, as it may deem necessary to assist in forensic investigations.

  • All DNA labs are required to share DNA data prepared and maintained by it with the National DNA Data Bank and the Regional DNA Data Bank.

  • Every DNA Data Bank shall maintain the following indices for various categories of data, namely:

o    a crime scene index
o    a suspects' index or undertrials' index
o    an offenders' index
o    a missing persons' index
o    unknown deceased persons' index

  • The Bill also provides for sharing of DNA profiles with foreign Government or international organization.

  • There is a provision of penalty for unlawful access to information in DNA Data Bank and also for destruction, alterations, contamination or tampering with biological evidence.

(Press Information Bureau, Ministry of Science & Technology, Jan. 8, 2019)

Dr KK Aggarwal
Padma Shri Awardee
President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)
Group Editor-in-Chief IJCP Publications
President Heart Care Foundation of India
Past National President IMA

Saturday, January 12, 2019

For HIV, undetectable is equal to untransmittable

The National Institutes of Health (NIH) has said that the Undetectable = Untransmittable (U=U) concept for HIV is a scientifically sound concept. Officials from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) have reviewed results from large clinical trials and cohort studies for U=U, which validate the concept, in an article published in JAMA, Jan. 10, 2019.

U=U means that people living with HIV who have achieved and maintained an undetectable viral load (less than 40 copies in one ml of blood)) by taking and adhering to antiretroviral therapy (ART) as prescribed cannot sexually transmit the virus to others.  The U=U initiative was launched in 2016 by the Prevention Access Campaign with the goal of ending the HIV/AIDS pandemic as well as HIV-related stigma. As a prevention strategy, this is often referred to as Treatment as Prevention

The landmark NIH-funded HIV Prevention Trials Network (HPTN) 052 clinical trial showed that no linked HIV transmissions occurred among HIV serodifferent heterosexual couples when the partner living with HIV had a durably suppressed viral load. These findings were further confirmed by the PARTNER (1 and 2) and Opposites Attract studies, which extended these findings to male-male couples.

Validation of the HIV treatment as prevention strategy and acceptance of the U=U concept as scientifically sound have numerous behavioral, social and legal implications, says NHI.

U=U can help control the HIV pandemic by preventing HIV transmission, and it can reduce the stigma that many people with HIV face. The success of U=U as an HIV prevention method depends on achieving and maintaining an undetectable viral load by taking ART daily as prescribed. 

Implementing programs that help patients remain in care and addressing the barriers to daily therapy can enhance the overall success of U=U.

In September 2017, the Division of HIV/AIDS Prevention, US Centers for Disease Control and Prevention (CDC) has also said that “people who take ART daily as prescribed and achieve and maintain an undetectable viral load have effectively no risk of sexually transmitting the virus to an HIV-negative partner”.

(Source: NIH)

Dr KK Aggarwal
Padma Shri Awardee
President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)
Group Editor-in-Chief IJCP Publications
President Heart Care Foundation of India
Past National President IMA

Decapitation of fetus during the delivery process

JAISALMER (TNN, Jan 11, 2019): The Rajasthan health minister Raghu Sharma ordered an inquiry into an incident in which the nursing staff of a health centre in Jaisalmer pulled out a baby with brutal force, severing its head.

Two male nurses have also been suspended. The incident occurred on Monday at Ramgarh primary health centre (PHC) in Jaisalmer. The compounder allegedly pulled out the baby during delivery using force, leaving the baby’s head in the womb.

Late on Thursday night, the department sent Dr Nikhil Sharma, in-charge of the Ramgarh PHC, to awaiting posting order. Health minister Raghu Sharma said, “Those guilty will be punished and strict action will be taken after investigation.” The incident happened on January 7, when two male nurses posted at Ramgarh PHC, pulled the baby out so fiercely that the infant’s head remained inside the uterus of the woman. The woman, 24-year-old Deeksha Kanwar, had to be rushed to Jodhpur, where the doctors operated upon her and removed the baby’s head

Delivery conducted sans presence of a doctor

On Wednesday, a case was filed under IPC sections 304 A (causing death by negligence) and 336 (act endangering life or personal safety) against the two staffers of Ramgarh PHC. A mother of three kids, this was Deeksha’s fourth delivery. The staff did not inform the family about her situation and referred her first to Jaisalmer. She was then sent to Jodhpur in a serious condition.

Despite being a high-risk case, the two nurses on duty—Amritram and Jhunjhar Ram—tried to deliver the chid of seven-month pregnant Deeksha without the presence of a doctor.

After the incident, they asked family members to take the woman to Jaisalmer claiming that the opening of the womb had closed and it was difficult to take the umbilical cord out. They hid the body of the baby and handed it over only after a police complaint was registered by the family. The family came to know about it after they were informed by the doctors in Jodhpur, who surgically removed the baby’s head. The family reached Ramgarh police station on Wednesday and lodged a case against the two nurses.

Chief medical health officer, Jaisalmer, Dr B L Bunkar said, “I visited Ramgarh and investigated the matter. There were two male nurses present when the woman was brought to the PHC before midnight, on the intervening night of January 6 and 7. Since the gynaecologist was on leave, the nursing staff handled the case. The baby was half out when the pregnant woman was brought to the PHC.It was a pre-term baby,” he added. Health department joint director (Jodhpur) Dr S K Parmar on Thursday rushed to Jaisalmer from Jodhpur to investigate the matter. “I will prepare a complete report on the incident and hand it over to health directorate,” he said.

Our views

Rare, cases of fetal decapitation, occurring intrauterine or during delivery process have been reported in literature.

Fetal decapitation can be spontaneous or accidental (occur by force). It can also be therapeutic (for a nonviable fetus), where it has to be done only by an experienced obstetrician as it is a radical procedure. 

·         The case of decapitation of a live fetus during vacuum-assisted delivery was reported in the American Journal of Forensic Medicine in 2011, where excessive traction on the head of the full-term macrosomic fetus with shoulder dystocia resulted in overstretching of the neck up to the point of decapitation (Am J Forensic Med Pathol. 2011 Sep;32(3):245-7).

·         Congenital malformation may present as spontaneous intrauterine decapitation as has been described in a case report of an acephalic fetus in the Archives of Disease in Childhood.  According to the author, decapitation must occur during the 3rd month of gestation or later and is thought to be due to strangulation by a band of tissue of amniotic or chorionic origin (Arch Dis Child. 1967;42(226):636-41).

·         Ledall et al have also reported subtotal decapitation of a fetus in the course of normal delivery with very peculiar bone dystrophy due to disturbance of intrauterine metabolism of tissue polysaccharides. (Bull Fed Soc Gynecol Obstet Lang Fr. 1964 Nov-Dec;16:549-51).

·         Lymphangioma of the axilla as an obstacle to delivery has also been reported (Geburtshilfe Frauenheilkd. 1956 Aug;16(8):706-8).

Decapitation can also be therapeutic. Marsden et al reported four cases of impacted transverse lie in late labor as illustrative of clinical situations where decapitation of a dead fetus in a transverse lie is a practical alternative to Caesarean section (Aust N Z J Obstet Gynaecol. 1982 Feb;22(1):46-9).

We have discussed here the causes of fetal decapitation and not gone into the merits of the case.

It may not be right to straightaway allege criminal medical negligence in this case without ascertaining the facts.

The case needs to be examined in detail. A thorough scrutiny of the facts and circumstances is required before ascribing blame. The training and skill or competency of the doctor/nurses or the hospital has to be taken into account.

However, this case re-emphasizes the significance of transparency, documentation/video recording in day to day practice. If the nursing staff has withheld information from the family, then this is a blunder. 

Fetal decapitation has been described in literature; this means that it is a known complication of delivery. And, complications are always lessons learned.

Dr KK Aggarwal
Padma Shri Awardee
President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)
Group Editor-in-Chief IJCP Publications
President Heart Care Foundation of India
Past National President IMA

Friday, January 11, 2019

59 new drugs approved by US FDA in 2018

Last year, the US FDA approved a record 59 new drugs, which included 19 first-in-class agents, 34 novel drugs for rare diseases, and a record seven biosimilars.

In 2017, 46 new drugs had been approved; in 2016, 22 drugs received the FDA green signal and in between 2009 and 2017, on an average 33 new drugs were accorded FDA approval.

Here is a list of the drugs approved by the FDA in 2018.

To treat paroxysmal nocturnal hemoglobinuria (PNH)
To treat blastic plasmacytoid dendritic cell neoplasm (BPDCN)
calaspargase pegol-mknl
To treat acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years
To treat chronic idiopathic constipation
To treat patients who have relapsed or refractory acute myeloid leukemia (AML)
To treat  Lambert-Eaton myasthenic syndrome in adults
To treat patients whose cancers have a specific genetic feature (biomarker)
To treat newly-diagnosed AML in adult patients
To treat primary hemophagocytic lymphohistiocytosis  
To treat travelers’ diarrhea
To treat patients with chronic obstructive pulmonary disease (COPD)
To treat patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer
baloxavir marboxil
For the treatment of acute uncomplicated influenza in patients who have been symptomatic for no more than 48 hours
For the treatment of locally advanced or metastatic breast cancer patients with a germline BRCA mutation
To treat polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults
To treat Adenosine Deaminase-Severe Combined Immuno-deficiency (ADA-SCID)
To treat community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections
To treat inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years 
To treat cutaneous squamous cell carcinoma
To treat metastatic non-small-cell lung cancer
For the preventive treatment of migraine in adults
To treat relapsed or refractory chronic lymphocytic leukemia, small lymphocytic lymphoma and follicular lymphoma
For the preventive treatment of migraine in adults
moxetumomab pasudotox-tdfk
To treat hairy cell leukemia
To treat HIV-1 infection in adult patients
To treat complicated intra-abdominal infections in patients ≥ 18 years 
To treat types I and II hereditary angioedema
To treat neurotrophic keratitis
To treat seizures associated with Dravet syndrome in patients 2 years taking clobazam
To treat adults with Fabry disease
segesterone acetate and ethinyl estradiol vaginal system
New vaginal ring used to prevent pregnancy for an entire year 
To treat the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adult patients
To treat two rare types of non-Hodgkin lymphoma
To treat thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure
fish oil triglycerides
As a source of calories and fatty acids in pediatric patients with parenteral nutrition-associated cholestasis
elagolix sodium
For the management of moderate to severe pain associated with endometriosis
For the radical cure (prevention of relapse) of Plasmodium vivax malaria
To treat patients with relapsed or refractory acute myeloid leukemia 
To treat smallpox
To treat unresectable or metastatic melanoma 
To treat unresectable or metastatic melanoma 
To treat adults with complicated urinary tract infections
To treat rare, severe forms of epilepsy
To treat onchocerciasis due to Onchocerca volvulus in patients aged 12 years 
To treat moderately to severely active rheumatoid arthritis
To treat adults with a rare and serious genetic disease known as phenylketonuria 
To treat low blood platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure
sodium zirconium cyclosilicate
To treat hyperkalemia
For the preventive treatment for migraine
lofexidine hydrochloride
For the non-opioid treatment for management of opioid withdrawal symptoms in adults
fosnetupitant and palonosetron
To prevent acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy
To treat adults and children aged  1 year with x-linked hypophosphatemia (XLH), a rare, inherited form of rickets
To treat thrombocytopenia in adult patients with persistent or chronic immune thrombocytopenia (ITP)
To treat adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy
To treat HIV patients who have limited treatment options
To treat a certain type of prostate cancer using novel clinical trial endpoint
tezacaftor; ivacaftor
To treat cystic fibrosis in patients aged  12 years 
bictegravir, embitcitabine, tenofovir alafenamide
To treat infection in adults who have no antiretroviral treatment history or to replace the current antiretroviral regimen
lutetium Lu 177 dotatate
To treat a type of cancer that affects the pancreas or gastrointestinal tract "gastro-enteropancreatic neuroendocrine tumors" (GEP-NETs)

Seven new Biosimilars approved

·         Fulphila (pegfilgrastim-jmdb) and Udenyca (pegfilgrastim-cbqv), respectively the first and second biosimilars to Neulasta
·         Herzuma (trastuzumab-abtr), the second biosimilar to Herceptin
·         Hyrimoz (adalimumab-adaz), the third biosimilar to Humira 
·         Nivestym (filgrastim-aafi), the second biosimilar to Neupogen 
·         Retacrit (epoetin alfa-epbx), the first biosimilar to Epogen/Procrit 
·         Truxima (rituximab-abbs), the first biosimilar to Rituxan

(Source: US FDA, Medscape)

Dr KK Aggarwal
Padma Shri Awardee
President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)
Group Editor-in-Chief IJCP Publications
President Heart Care Foundation of India
Past National President IMA