Excerpts from: Cohen PA. Probiotic Safety—No Guarantees. JAMA Intern Med. 2018;178(12):1577–1578

Isolated live bugs are being promoted for their purported beneficial or “probiotic” properties. Claims such as these are all too common: “boosts digestive health”; “supports the immune system”; “friendly bacteria that benefit your skin, health & beauty”.

Do probiotics really work? Are there safety concerns we should be worried about?

Creative marketing and a general fascination for gut bacteria have combined to create a huge market for probiotics. Perhaps surprisingly, to sell a product that contains live microorganisms there is no legal requirement to provide evidence that it works or, importantly, that it is safe.

What is a probiotic?

The World Health Organization defines probiotics as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.”

The state of the evidence

Certain live microorganisms do have well-defined health benefits, and emerging literature supports the use of select strains of bacteria and yeast to treat specific medical conditions. The yeast Saccharomyces boulardii, for example, reduces the rates of antibiotic-associated diarrhea in children and can decrease rates of recurrent Clostridium difficile infections in adults, when combined with antibiotics. Most microorganisms used in the production of food, however, do not have proven health benefits, and their safety, when sold as probiotic supplements, has not been fully established.

Although preliminary evidence supports the use of specific strains of probiotics in certain clinical settings, such as preventing C. difficile and antibiotic-associated diarrhea, widespread use, particularly among people who are healthy, has greatly outpaced the science.

Probiotics are promoted to assist healthy adults, adolescents, and children to maintain normal intestinal function and to sustain cardiovascular, respiratory, immunologic, reproductive, and even psychological health. Despite the advertised indications, there are no large, long-term clinical trials proving that probiotics offer clinical benefits for people who are already healthy.

For instance, a comprehensive review of relevant literature published earlier this year concluded that “the feasibility of probiotics consumption to provide benefits in healthy adults requires further investigation.” In other words, there may be benefits, but the evidence simply does not exist to definitively say either way.

What are the possible dangers?

Over the years, dozens of case reports have underscored the potential hazards of probiotic supplementation. Risks include fungemia and bacteremia — the presence of fungi or bacteria in the blood, respectively. Individuals with compromised immune systems are most at risk, including the very young and old. These organisms have evolved to infect, after all. Because many probiotic trials do not report adverse events sufficiently, the exact scope of this problem is not known. Aside from the risk of opportunistic infections sparked by probiotic consumption, there is the potential threat of low quality and contaminated products.

Take-home message

Consumers and physicians should not assume that the label on probiotic supplements provides adequate information to determine if consuming the live microorganism is worth the risk

Poor oral hygiene is the #1 risk factor for bad breath. In most cases, the cause can be traced to the mouth. The smell is mainly caused by volatile sulfur compounds (VSC) produced by bacteria.

The patient is often unaware of the problem and it can be worsened by mouth breathing. Transient oral malodour on awakening is a natural phenomenon.

Halitosis may cause significant social impairment, fear of social situations and social withdrawal. For most patients, halitosis may be more of a social vs medical problem.

Management of halitosis usually involves identifying and treating the specific cause. Oral hygiene should be recommended to every patient. Stimulation of salivary flow and use of refreshing mouthwashes or gargles may benefit certain patients

Causes of bad breath

Poor oral hygiene, dental caries, periodontal diseases, and difficulty in cleaning prostheses.

Reduced salivation and drying of the mouth often associated with Sjögren’s syndrome, Radiotherapy and post-operative conditions, Anticholinergic drugs

Bad-smelling nutrients, drugs, and stimulants and their degradation products e.g. Garlic, Tobacco, Alcohol, Isosorbide nitrate, Disulfiram

Infection and putrefaction involving salivary glands, tongue, ulcers and lesions of the oral mucosa

Infection of the tonsils, adenoids or lingual tonsil

Tonsillary plugs: whitish or yellowish foul-smelling grainy mass is accumulated in the tonsillary crypts and is shed by pressure on the crypt.

Retropharyngeal or nasopharyngeal accumulation of mucus and pus, adenoids (cause mouth breathing, particularly in children), maxillary sinusitis

Nasal tumours, foreign bodies, other causes increasing mouth breathing

Atrophic rhinitis and ozaena

Oesophageal diverticles, achalasia, reflux disease

Bronchitis, bronchiectasis, pulmonary empyema

Some systemic diseases namely diabetes, renal and hepatic failure

If no outside person has reported on the patient having oral malodour, the patient may suffer from a disturbance of the sense of smell or from olfactory hallucinations.

Treatment

Treatment is aetiology-specific. Severe tonsil-associated malodour problem may warrant tonsillectomy.

When no specific treatable cause is found, the management consists of attempts to increase salivary secretion, to decrease the amount of bacteria in the mouth and to mask the odour:

• Good oral hygiene, tongue brushing or scraping
• Stimulation of salivation using chewing gum or lozenges; artificial saliva
• Non-alcoholic antimicrobial mouthwashes and gargles. Mouthwashes and toothpastes containing e.g. chlorhexidine, cetylpyridinium or triclosan temporarily decrease the amount of odour-producing bacteria. Disadvantages of chlorhexidine include unpleasant taste and staining of teeth.
• Lozenges, mouthwashes and sprays intended for masking the odour have a momentary effect only.

A U.S. Food and Drug Administration (FDA) review found that fluoroquinolone antibiotics can increase the occurrence of rare but serious events of ruptures or tears in the main artery of the body, called the aorta.  These tears, called aortic dissections, or ruptures of an aortic aneurysm can lead to dangerous bleeding or even death.  They can occur with fluoroquinolones for systemic use given by mouth or through an injection.

Fluoroquinolones should not be used in patients at increased risk unless there are no other treatment options available.  People at increased risk include those with a history of blockages or aneurysms (abnormal bulges) of the aorta or other blood vessels, high blood pressure, certain genetic disorders that involve blood vessel changes, and the elderly.  We are requiring that a new warning about this risk be added to the prescribing information and patient Medication Guide for all fluoroquinolones.

Fluoroquinolone antibiotics are approved to treat certain bacterial infections and have been used for more than 30 years.  They work by killing or stopping the growth of bacteria that can cause illness.  Without treatment, some infections can spread and lead to serious health problems (see List of Currently Available FDA-Approved Systemic Fluoroquinolones).

Health care professionals should avoid prescribing fluoroquinolone antibiotics to patients who have an aortic aneurysm or are at risk for an aortic aneurysm, such as patients with peripheral atherosclerotic vascular diseases, hypertension, certain genetic conditions such as Marfan syndrome and Ehlers-Danlos syndrome, and elderly patients.  Prescribe fluoroquinolones to these patients only when no other treatment options are available.  Advise all patients to seek immediate medical treatment for any symptoms associated with aortic aneurysm.  Stop fluoroquinolone treatment immediately if a patient reports side effects suggestive of aortic aneurysm or dissection.

Patients should seek medical attention immediately by going to an emergency room or calling 911 if you experience sudden, severe, and constant pain in the stomach, chest or back.  Be aware that symptoms of an aortic aneurysm often do not show up until the aneurysm becomes large or bursts, so report any unusual side effects from taking fluoroquinolones to your health care professional immediately.  Before starting an antibiotic prescription, inform your health care professional if you have a history of aneurysms, blockages or hardening of the arteries, high blood pressure, or genetic conditions such as Marfan syndrome or Ehlers-Danlos syndrome.  If you have been prescribed a fluoroquinolone to treat an infection, do not stop the antibiotic without first talking to your health care professional.

We reviewed cases reported to FDA* and four published observational studies1,2,3,4 that showed an increased risk of aortic aneurysm or dissection associated with fluoroquinolone use (see Data Summary).  How some of the studies were designed or carried out, and the ways the data were analyzed could affect the study findings; however, taken together, the results of all four studies provide consistent evidence of an association between fluoroquinolone use and aortic aneurysm or dissection.  The underlying mechanism for this risk cannot be determined from these studies, and the background risk of aortic aneurysm can vary depending on the population.  The background risk has been estimated from nine aortic aneurysm events per 100,000 people per year in the general population to 300 aortic aneurysm events per 100,000 people per year in individuals at highest risk.  Because multiple studies showed higher rates of about twice the risk of aortic aneurysm rupture and dissection in those taking fluoroquinolones, FDA determined the warnings were warranted to alert health care professionals and patients.

We communicated safety information associated with fluoroquinolones in July 2018 (significant decreases in blood sugar and certain mental health side effects), July 2016 (disabling side effects of the tendons, muscles, joints, nerves, and central nervous system), May 2016 (restricting use for certain uncomplicated infections), August 2013 (peripheral neuropathy), and July 2008 (tendinitis and tendon rupture)

Further reading: FDA Drug Safety Communication, December 20, 2018

A refresher for every clinician

Contrast media (contrast agents or dyes) are widely used as adjuncts to diagnostic visualisation techniques such as radiography (X-ray), magnetic resonance imaging (MRI), and ultrasound imaging. These agents are broadly classified based on WHO’s ATC system as shown below:

1) Radiocontrast media, Iodinated e.g., Diatrizoic acid (Amidotrizoate or Diatrizoate), Iohexol, Iopamidol, Iopromide, Iotroxic acid (or Meglumine iotroxate)

2) Radiocontrast media, Non-iodinated e.g., Barium sulfate

3) Magnetic resonance imaging (MRI) contrast media e.g., Gadobutrol, Gadopentetic acid

4) Ultrasound contrast media e.g., Optison® (GE Healthcare) – contains an albumin shell and octafluoropropane gas core

RADIOGRAPHIC OR X-RAY CONTRAST MEDIA (RADIOCONTRAST MEDIA)

Radiocontrast media are needed for delineating soft tissue structures such as blood vessels, stomach, bowel loops, and body cavities that are not otherwise visualized by standard X-ray examination. The contrast media in this group, which all contain heavy atoms (metal or iodine), absorb a significantly different amount of X-rays than the surrounding soft tissue, thereby making the exposed structures visible on radiographs.

The radiocontrast media are subdivided into iodinated (iodine-containing) and non-iodinated (metal-containing) compounds.

Radiocontrast media, Non-iodinated

Barium sulfate is a metal salt which is chiefly used for gastrointestinal imaging. It is not absorbed by the body and does not interfere with stomach or bowel secretion or produce misleading radiographic artefacts. Barium sulfate may be used in either single- or double-contrast techniques or computer-assisted axial tomography.

Single-contrast technique can be positive or negative. Positive contrast imaging is achieved by introducing a contrast medium (i.e., barium sulfate) into the GI tract to increase the density and enhance absorption of the X-rays. In negative contrast imaging, a gas (air, oxygen, or carbon dioxide) may be used to allow the X-rays to penetrate more easily. In double contrast examinations, both gas and contrast medium are used together. The gas is introduced into the GI tract by using suspensions of barium sulfate-containing carbon dioxide or by using separate gas-producing preparations based on sodium bicarbonate. Air administered through a GI tube can be used as an alternative to carbon dioxide to achieve a double-contrast effect.

Radiocontrast media, Iodinated

Iodinated contrast media all have a common functional group – tri-iodinated benzene ring. The 3 iodine atoms covalently bonded to benzene are essential for absorbing X-rays and help reduce the risk of toxic effects from free iodide. Based on the benzene ring structure and the presence (ionic) or absence (non-ionic) of carboxylate ion (-COO^–), these agents are classified into 4 categories:

• Ionic high-osmolarity monomers: one tri-iodinated benzene ring plus carboxylate ion. These agents are water-soluble, nephrotropic, high-osmolar radiocontrast media e.g., Meglumine amidotrizoate, Sodium amidotrizoate
• Ionic low-osmolality dimers: two tri-iodinated benzene rings plus carboxylate ion. These agents are water-soluble, hepatotropic, low-osmolar radiocontrast media e.g., Meglumine iotroxate
• Non-ionic low-osmolality monomers: one tri-iodinated benzene ring without carboxylate ion. These agents are water-soluble, nephrotropic, low-osmolar radiocontrast media e.g., Iohexol, Iopamidol, Iopromide
• Non-ionic iso-osmolar dimers: two tri-iodinated benzene ring without carboxylate ion. These agents are water-soluble, nephrotropic, iso-osmolar, high-viscosity radiocontrast media e.g., Iodixanol

The ionic agents have negative charge conferred by the carboxylate ion and are usually available in salt forms e.g., as sodium or meglumine salts of tri-iodinated benzoic acid.

The first-generation agents are the ionic monomeric media e.g., Amidotrizoates; available as Meglumine amidotrizoate and Sodium amidotrizoate. Although both salts have been used alone in diagnostic radiography (including computer-assisted axial tomography), a mixture of both is often preferred so as to minimize adverse effects and to improve the quality of the examination. Amidotrizoates are used in a wide range of procedures including urography, and examination of the gallbladder, biliary ducts, and spleen. Owing to their high osmolality, they are associated with a high incidence of adverse effects.

The osmolality for a given radiodensity which depends on iodine concentration, can be reduced by using an ionic dimeric medium such as Meglumine iotroxate, which contains twice the number of iodine atoms in a molecule, or by using a non-ionic monomeric media such as Iohexol, Iopamidol or Iopromide. Low osmolality radiocontrast media such as iohexol are associated with a reduction in some adverse effects (see below), but they are generally more expensive. Iohexol is used for a wide range of diagnostic procedures including urography, angiography and arthrography, and also in computer-assisted axial tomography. Meglumine iotroxate is excreted into the bile after intravenous administration and is used for cholecystography and cholangiography.

Non-ionic dimeric media (e.g., Iodixanol) have the best ratio of radiodensity to osmolality but they tend to be more viscous. Increased viscosity can make intravascular injection more difficult, especially at high flow rates. This may be less an issue for nonvascular administration. More viscous contrast media are routinely warmed to 37°C so that adequate flow rates can be attained during intravenous injection.

MAGNETIC RESONANCE IMAGING (MRI) CONTRAST MEDIA

Contrast media may be used to enhance magnetic resonance images. MR contrast agents are subdivided based on magnetic properties:

(a) Paramagnetic contrast media e.g., Gadobutrol, Gadopentetic acid, Ferric ammonium citrate

(b) Superparamagnetic contrast media e.g., Ferumoxsil, Iron oxide (nanoparticles)

Paramagnetic compounds contain gadolinium or manganese and are used as complexes or chelates to reduce their toxicity. Example of gadolinium-based contrast media is gadopentetic acid. Superparamagnetic contrast media contain coated particles of iron compounds.

ULTRASOUND CONTRAST MEDIA

Contrast agents used to enhance ultrasound imaging consist of gas-filled microbubbles which provide a gas-liquid interface that reflects sound more effectively than blood alone, allowing blood flow to be more easily detected. The microbubbles consist of air or another inert gas and an outer shell (e.g., albumin, galactose). Example of commercially available microbubble contrast agent is Optison® by GE Healthcare. It has an albumin shell and octafluoropropane gas core.

ADVERSE EFFECTS OF CONTRAST MEDIA & THEIR MANAGEMENT

Excerpts from ESUR (European Society of Urogenital Radiology) Guidelines on Contrast Media

Contrast media generally have similar adverse effect profiles, but the incidence tends to be higher with the high-osmolality agents. Osmolality depends on the iodine concentration and for a given iodine content, this is highest for the ionic monomers and lowest for non-ionic dimers.

The adverse reactions are broadly classified as non-renal and renal.

Non-renal adverse reactions

Acute adverse reactions occur within 1 hour of contrast medium injection; usually mild to moderate. Common minor adverse reactions include rash, pain at the injection site, nausea, vomiting, and minor hemodynamic changes, which are all usually self-limiting. Acute severe reactions are usually anaphylactic or anaphylactoid and the risk is usually greatest in patients with asthma, atopy, or a previous reaction to an iodinated contrast agent.

Delayed adverse reaction to intravascular iodine-based contrast medium is defined as a reaction which occurs 1 h to 1 week after contrast medium injection. Late skin reactions similar in type to other drug-induced eruptions. Maculopapular rashes, erythema, swelling and pruritus are most common. Most skin reactions are mild to moderate and self-limiting. Management is similar to other drug-induced skin reactions e.g. antihistamines, topical steroids and emollients

Very late adverse reactions usually occur more than 1 week after contrast medium injection. They may include thyrotoxicosis (due to iodine-based contrast media) and nephrogenic systemic fibrosis (or NSF, due to gadolinium-based contrast media).

NOTE: The risk of an acute reaction to a gadolinium-based MRI contrast agent is lower than the risk with an iodine-based contrast agent, but severe reactions to gadolinium-based contrast media may occur.

Delayed skin reactions of the type which occur after iodine-based contrast media have not been described after gadolinium-based and ultrasound contrast media.

Factors predisposing to nonrenal adverse reactions to contrast media

• Previous adverse reactions
• History of asthma or bronchospasm
• History of allergy or atopy
• Risk of acute reactions usually greater with high-osmolality ionic contrast media; risk of delayed reactions is higher with the non-ionic dimers.
• Cardiac disease
• Dehydration
• Haematological and metabolic conditions (sickle cell anaemia, patients with thrombotic tendency, e.g. polycythaemia, myelomatosis or phaeochromocytoma)
• Renal disease
• Neonates, very old and infirm patients
• Anxiety and apprehension
• Sun exposure may increase the risk of developing delayed cutaneous reaction
• Medications (beta-blockers, interleukin 2 (a potent stimulator of the immune system), aspirin, NSAIDs)

Guidelines for first-line treatment of acute nonrenal reactions to all contrast media

The same reactions are seen after iodine- and gadolinium-based contrast agents and after ultrasound contrast agents. The incidence is highest after iodine-based contrast agents and lowest after ultrasound agents.

Nausea/Vomiting
Transient: Supportive treatment
Severe, protracted: Appropriate antiemetic drugs should be considered.

Urticaria
Scattered, transient: Supportive treatment including observation.
Scattered, protracted: Appropriate H1-antihistamine intramuscularly or intravenously should be considered. Drowsiness and/or hypotension may occur.
Generalized: Appropriate H1-antihistamine intramuscularly or intravenously should be given. Drowsiness and/or hypotension may occur. Consider Adrenaline 1:1,000, 0.1-0.3 mL (0.1-0.3 mg) intramuscularly in adults, 50% of adult dose to pediatric patients between 6 and 12 years old and 25% of adult dose to pediatric patients below 6 years old. Repeat as needed.

Bronchospasm

1. Oxygen by mask (6-10 L/min)
2. β-2-agonist metered-dose inhaler (2-3 deep inhalations)
3. Adrenaline

Normal blood pressure
Intramuscular: 1:1,000, 0.1-0.3 mL (0.1-0.3 mg) [use smaller dose in a patient with coronary artery disease or elderly patient]
In pediatric patients: 50% of adult dose to pediatric patients between 6 and 12 years old and 25% of adult dose to pediatric patients below 6 years old. Repeat as needed.

Decreased blood pressure
Intramuscular: 1:1,000, 0.5 mL (0.5 mg),
In pediatric patients: 6-12 years: 0.3 mL (0.3 mg) intramuscularly; <6 years: 0.15 mL (0.15 mg) intramuscularly

Laryngeal edema

1. Oxygen by mask (6 – 10 L/min)
2. Intramuscular adrenaline (1:1,000), 0.5 mL (0.5 mg) for adults, repeat as needed.

In pediatric patients: 6-12 years: 0.3 mL (0.3 mg) intramuscularly; <6 years: 0.15 mL (0.15 mg) intra

Hypotension
Isolated hypotension

1. Elevate patient’s legs
2. Oxygen by mask (6-10 L/min)
3. Intravenous fluid: rapidly, normal saline or Ringer’s solution
4. If unresponsive: Adrenaline: 1:1,000, 0.5 mL (0.5 mg) intramuscularly, repeat as needed
   In pediatric patients: 6-12 years: 0.3 mL (0.3 mg) intramuscularly; <6 years: 0.15 mL (0.15 mg) intramuscularly

Vagal reaction (hypotension and bradycardia)

1. Elevate patient’s legs
2. Oxygen by mask (6-10 L/min)
3. Atropine 0.6-1.0 mg intravenously, repeat if necessary after 3-5 min, to 3 mg total (0.04 mg/kg) in adults.
   In pediatric patients give 0.02 mg/kg intravenously (max. 0.6 mg per dose), repeat if necessary to 2 mg total.
4. Intravenous fluids: rapidly, normal saline or Ringer’s solution

Generalized anaphylactoid reaction

1. Ensure patent airway as needed
2. Elevate patient’s legs if hypotensive
3. Oxygen by mask (6–10 L/min)
4. Intramuscular Adrenaline (1:1,000), 0.5 mL (0.5 mg) in adults. Repeat as needed.
   In pediatric patients: 6-12 years: 0.3 mL (0.3 mg) intramuscularly; <6 years: 0.15 mL (0.15 mg) intramuscularly
5. Intravenous fluids (e.g. normal saline, Ringer’s solution).
6. H1-blocker e.g. Diphenhydramine 25-50 mg intravenously

Renal adverse reactions

Contrast-induced nephropathy (CIN) is a condition in which a decrease in renal function occurs within 3 days of the intravascular administration of a CM in the absence of an alternative aetiology. An increase in serum creatinine by more than 25% or 44 μmol/L (0.5 mg/dL) indicates CIN.

NOTE: The risk of nephrotoxicity is very low when gadolinium-based contrast media are used in approved doses.

Risk Factors for Contrast Medium-Induced Nephropathy

• Pre‐existing renal dysfunction, particularly when the reduction in renal function is secondary to diabetic nephropathy
• Conditions associated with reduced renal perfusion e.g., dehydration, CHF, myocardial infarction.
• Age over 70 due to the reduction in renal mass, function and perfusion which occurs with age
• Concurrent use of nephrotoxic drugs e.g., NSAIDs and aminoglycosides, potentiates the nephrotoxic effects of contrast media
• Intra-arterial administration of contrast medium. Intrarenal concentration of contrast media is much higher immediately after intra‐arterial injection than after intravenous administration
• High osmolality agents
• Large doses of contrast medium
• Multiple contrast medium administrations within a few days

DRUG INTERACTIONS

Co-administration of Iodine-based contrast media with Metformin

Metformin and iodine-based contrast media are eliminated via the kidneys. Administration of contrast agents in patients receiving Metformin can precipitate lactic acidosis, especially in patients with abnormal renal function. Symptoms of lactic acidosis include vomiting, somnolence, nausea, epigastric pain, anorexia, hyperpnoea, lethargy, diarrhoea and thirst.

Below is an outline of ESUR guideline recommendations for the use of iodinated contrast agents in patients receiving Metformin:

• Patients (eGFR ≥60 mL/min/1.73m²): Continue Metformin normally
• Patients receiving intravenous contrast medium (eGFR ≥45 mL/min/1.73 m²): Continue Metformin normally
• Patients receiving intra-arterial or intravenous contrast medium (eGFR 30-44 mL/min/1.73 m²): Stop Metformin 48 h before contrast medium and only restart Metformin 48 h after contrast medium if renal function has not deteriorated
• Patients (eGFR <30 mL/min/1.73 m² or with an intercurrent illness causing reduced liver function or hypoxia): Metformin is contra-indicated and iodine-based contrast media should be avoided.
• Emergency patients: Metformin should be stopped from the time of contrast medium administration. After the procedure, the patient should be monitored for signs of lactic acidosis. Metformin should be restarted 48 h after contrast medium if serum creatinine/eGFR is unchanged from the pre-imaging level.

NOTE: No special precautions are necessary when diabetic patients on metformin are given gadolinium-based contrast medium

Interaction with other drugs

• Nephrotoxic drugs: Cyclosporine, Cisplatin, Aminoglycosides, NSAIDs
• Beta-blockers: β-blockers may impair the management of bronchospasm and the response to adrenaline
• Do not mix contrast media with other drugs in tubes and syringes

References:

1. Pasternak JJ, Williamson EE. Clinical Pharmacology, Uses, and Adverse Reactions of Iodinated Contrast Agents: A Primer for the Non-radiologist. Mayo Clin Proc. 2012 Apr;87(4):390–402.
2. European Society of Urogenital Radiology [Internet]. [cited 2018 Nov 16]. Available from: http://www.esur.org/guidelines/
3. Thomsen HS, Morcos SK. Radiographic contrast media: Radiographic Contrast Media. BJU Int. 2002 Jan 2;86:1–10

The U.S. Food and Drug Administration today approved Aemcolo (rifamycin), an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), not complicated by fever or blood in the stool.

“Travelers’ diarrhea affects millions of people each year and having treatment options for this condition can help reduce symptoms of the condition,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Travelers’ diarrhea is the most common travel-related illness, affecting an estimated 10 to 40 percent of travelers worldwide each year. Travelers’ diarrhea is defined by having three or more unformed stools in 24 hours, in a person who is traveling. It is caused by a variety of pathogens, but most commonly bacteria found in food and water. The highest-risk destinations are in most of Asia as well as the Middle East, Africa, Mexico, and Central and South America.

Aemcolo is rifamycin SV engineered with the MMX® technology which allows the antibiotic to be delivered directly into the colon, avoiding unwanted effects on the beneficial bacterial flora living in the upper portions of the gastrointestinal tract. The specific dissolution profile of Aemcolo tablets is thought to increase the colonic disposition of the antibiotic so that an optimized intestinal concentration is achieved thus abating its systemic absorption in the small intestine.

The efficacy of Aemcolo was demonstrated in a randomized, placebo-controlled clinical trial in 264 adults with travelers’ diarrhea in Guatemala and Mexico. It showed that Aemcolo significantly reduced symptoms of travelers’ diarrhea compared to the placebo.

The safety of Aemcolo, taken orally over three or four days, was evaluated in 619 adults with travelers’ diarrhea in two controlled clinical trials. The most common adverse reactions with Aemcolo were headache and constipation.

Aemcolo was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool or diarrhea due to pathogens other than noninvasive strains of E. coli and is not recommended for use in such patients. Aemcolo should not be used in patients with a known hypersensitivity to rifamycin, any of the other rifamycin class antimicrobial agents (e.g. rifaximin), or any of the components in Aemcolo.

The FDA granted Aemcolo a Qualified Infectious Disease Product (QIDP) designation. QIDP designation is given to antibacterial and antifungal drug products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, the Aemcolo marketing application was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame

The study funded by Canadian Institutes of Health Research showed that a pharmacist-led educational intervention resulted in greater discontinuation of inappropriate prescriptions compared with usual care after 6 months.

Key Points

Question: Can a consumer-targeted, pharmacist-led educational intervention reduce prescriptions for inappropriate medication among community-dwelling older adults?

Findings: In this cluster randomized trial that included 489 older adults, the percentage achieving discontinuation of a targeted inappropriate prescription at 6 months was 43% among patients receiving the intervention vs 12% receiving usual care, which represents a significant difference.

Meaning: A pharmacist-led intervention has the potential to reduce prescriptions for inappropriate medication in older adults.

Introduction

Inappropriate prescriptions continue to be frequently dispensed to older adults. It has been estimated that 29.0% of Medicare beneficiaries aged 65 years and older in the United States in 2015 and 31.1% of older adults in Canada in 2016 filled a prescription for at least 1 medication included in the 2015 American Geriatrics Society Beers Criteria list of drugs to avoid in older adults. Labelled as inappropriate because of the risk of harm and availability of safer treatments, inappropriate prescriptions can lead to adverse drug events, falls, cognitive impairment, and emergency hospitalizations.

Deprescribing is the act of reducing or stopping medication that is no longer necessary or that may cause harm. Primary care physicians express a lack of time, poor awareness of the harms of medications, and fear of withdrawal symptoms or patient criticism as barriers to deprescribing. Pharmacists can assist physicians in optimizing medication management in older adults. Medication reviews by a pharmacist followed by direct communication to the prescribing physician have been shown to result in safer prescribing practices. Patients can also initiate the deprescribing process. In a randomized clinical trial of 303 long-term users of benzodiazepine medications, providing education about the risks of benzodiazepine use compared with providing usual care resulted in an additional 23% of patients discontinuing their medication within 6 months. Patients who elected not to taper their medication cited physician or pharmacist discouragement as the major impediment. Streamlining communication and deprescribing efforts among patients, physicians, and pharmacists may augment shared accountability for safer prescribing while maintaining patient trust.

The objective of the D-PRESCRIBE (Developing Pharmacist-led Research to Educate and Sensitize Community Residents to the Inappropriate Prescriptions Burden in the Elderly) cluster randomized trial was to determine the effectiveness of a pharmacist-led intervention to educate older adults and their physicians about reducing inappropriate prescriptions.

Access to the full article available on JAMA Network

Sandoz Inc. Issues Voluntary Nationwide Recall of One Lot of Losartan Potassium and Hydrochlorothiazide Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

FDA is alerting patients and health care professionals to Sandoz’s voluntary recall of one lot – JB8912 – of losartan potassium and hydrochlorothiazide 100mg/25mg tablets, that contain losartan, an angiotensin II receptor blocker (ARB), and hydrochlorothiazide, a diuretic, used in combination for the treatment of hypertension. Sandoz’s product was made using an active pharmaceutical ingredient (API) that has tested positive for NDEA. The API was manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd, which is on import alert.

Sandoz’s losartan drug products make up less than 1% of the total losartan drug products in the U.S. market.

FDA continues to investigate the presence of NDEA and NDMA, which are probable human carcinogens, in ARBs and is taking swift action when it identifies unacceptable impurities in API and finished drug products.

FDA reminds patients taking this medication or any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor provides an alternative treatment option. It also is important to know not all ARBs contain NDEA or NDMA, so pharmacists may be able to provide a refill of medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition

Full text of the company announcement available here

FDA is alerting patients and healthcare professionals to ScieGen’s voluntary recall of certain lots of irbesartan, an angiotensin II receptor blocker (ARB), because they contain N-Nitrosodiethylamine (NDEA), a known animal and suspected human carcinogen (causes cancer). FDA laboratory testing confirmed NDEA in some lots of ScieGen’s irbesartan. This is the first non-valsartan drug product the agency has found to contain the NDEA impurity

Additionally, Aurobindo, which manufactures the active pharmaceutical ingredient (API) for ScieGen’s irbesartan products, is recalling all unexpired lots of its irbesartan API supplied to the U.S. market with NDEA. FDA and Aurobindo laboratory testing confirmed NDEA in certain lots of their irbesartan API.

The saga of contaminated “sartans” began in July, when some valsartan products manufactured by China’s Zhejiang Huahai Pharmaceuticals (ZHP) were found to be contaminated with another potential carcinogen, N-nitrosodimethylamine (NDMA). This led US and European regulators to pull all affected valsartan products from the market.

FDA reminds patients taking any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor provides an alternative treatment option. Not all ARBs contain NDEA or N-Nitrosodimethylamine (NDMA), a probable human carcinogen previously found in certain recalled valsartan products, so pharmacists may be able to provide a refill of medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition.

To date, ScieGen is the only manufacturer of irbesartan drug products found to contain NDEA. FDA continues to test all ARBs for the presence of impurities and has publicly posted two methods for manufacturers and regulatory agencies around the world to test their ARBs for the unexpected NDMA and NDEA impurities. The combined headspace method and the combined direct injection method can detect and quantify NDMA and NDEA simultaneously in ARB API and finished drug products.

FDA continues to work with API and drug manufacturers to ensure their products are not at risk for NDMA or NDEA formation. The agency reminds manufacturers they are responsible for developing and using suitable methods to detect impurities, including when they make changes to their manufacturing processes. If a manufacturer detects new or higher levels of impurities, they should fully evaluate the impurities and take action to ensure the product is safe for patients.

For additional information about ARB products, see:

• list of valsartan products under recall
• list of irbesartan products under recall

Therapeutic intermittent fasting may help eliminate the need for insulin and other glucose-lowering medications in patients with type 2 diabetes, a new case series suggests.

Findings from three cases were published online October 9 in BMJ Case Reports by Suleiman Furmli, MD, of the Department of Family Medicine at the University of Toronto, Ontario, Canada, and colleagues.

The three patients had all been referred to an intensive dietary management clinic and were taking at least 70 units/day of insulin. After several months of intermittent fasting — either on alternate days or three times weekly — all three were able to discontinue insulin while improving their glycemic control. They also lost substantial amounts of body weight and had reduced waist circumferences.

“Medically supervised, therapeutic fasting regimens can help reverse type 2 diabetes and minimize the use of pharmacological and possibly surgical interventions in patients with type 2 diabetes,” Furmli and colleagues write.

The patients were given 6 hours of training on diabetes and nutrition and specific instructions for fasting. They ate only dinner and consumed unlimited very low-calorie fluids on fasting days, and ate both lunch and dinner on nonfasting days. Low-carbohydrate meals were recommended when eating meals. They followed up with the treating physician every 2 weeks.

Success Times Three

Patient 1 was a 40-year-old man with type 2 diabetes for 20 years who also had hypertension and hypercholesterolemia. At baseline, he was taking metformin, canagliflozin, and long- and short-acting insulin. After fasting three times a week for 7 months, he was able to discontinue all the drugs except for canagliflozin, his HbA1c dropped from 12% to 7.5%, his weight was reduced from 84 kg to 74 kg (184 lb to 163 lb), and his weight circumference decreased from 100 cm to 87 cm (43 in to 34 in).

He reported having no difficulty with fasting and that he felt “excellent” on fasting days.

Patient 2 was a 52-year-old man with type 2 diabetes for 25 years as well as chronic kidney disease, prior renal cell carcinoma, hypertension, and hypercholesterolemia. He had been taking a fixed-dose insulin mix.

After following the same regimen as patient 1 for 11 months, patient 2 came off the insulin. His HbA1c dropped from 7.2% to 6.0%, his weight was reduced from 61 kg to 50 kg, and his waist circumference fell from 123 cm to 110 cm. He reported feeling “terrific.”

Patient 3, a 67-year-old man with type 2 diabetes for 10 years who also had hypertension and hypercholesterolemia, was taking metformin and pre-mixed insulin. After alternating fasting days for 11 months, he eliminated both diabetes medications, his HbA1c dropped from 6.8% to 6.2%, his weight dropped from 97 kg to 88 kg, and his waist circumference decreased from 123 cm to 110 cm. He said he found the fasting “easy,” that his carbohydrate cravings had disappeared, and that his energy levels were higher.

“Therapeutic fasting is an underutilized dietary intervention that can provide superior blood glucose reduction compared with standard pharmacological agents,” the authors conclude.

BMJ Case Reports. Published online October 9, 2018

Specific treatment recommendations for the common symptoms associated with cough and cold

Productive cough:

Characterized by the presence of excessive sputum and may be associated with various underlying diseases e.g. chronic bronchitis, Tuberculosis, LVF etc.

Treatment of the underlying cause recommended e.g. with antibiotics.

Avoid antitussives as suppression of cough can be harmful

Expectorants may help to reduce sputum viscosity so bronchial secretions can be expectorated. There are 2 types:

• Mucolytic expectorants e.g. Ambroxol, Acetylcysteine, Carbocysteine, Bromhexine.
• Mucokinetic expectorants e.g. Sodium or potassium citrate, Ammonium chloride, Potassium iodide, Guaifenesin, Tolu balsam.

Expectorants may cause bronchospasm in patients with asthma.

Non-productive cough:

Characterized by dry, irritating cough with little or no sputum.

Suppression of cough using antitussives (e.g. Dextromethorphan, Codeine) usually indicated

May cause excessive drowsiness

Postnasal drip cough:

A combination of first-generation antihistamine (e.g. diphenhydramine, chlorphenamine) and nasal decongestant (e.g. pseudoephedrine, phenylephrine) may be indicated. Antibiotics may be added if necessary for bacterial sinusitis.

Caution when using decongestants in patients with hypertension or other cardiovascular disease.

Asthmatic cough:

Short-acting beta-agonists (SABAs e.g. Salbutamol, Terbutaline) are usually indicated. Inhaled corticosteroids may be added depending on the severity.

GERD-associated cough:

H2RA (e.g. Ranitidine, Famotidine) or PPI (e.g. Omeprazole, Pantoprazole) are the treatments of choice. Non-drug measures include elevation bedhead, light dinner, diet modification, etc.

ACE inhibitor associated cough:

Substitute ACEI with ARB (e.g. Losartan). Antitussives not useful

Nasal congestion:

Systemic decongestants (e.g. Pseudoephedrine, Phenylephrine) or nasal decongestants (e.g. Oxymetazoline, Xylometazoline) may be useful.

They act indirectly to reduce blood flow, edema and swelling in the nasal area, thereby helping to alleviate nasal congestion.

Side effects may include rebound congestion, palpitations, tachycardia, burning sensation with topical agents.

Caution in patients with cardiovascular disease especially with the systemic agents.

Saline spray or drops may be effective alternatives and should be considered first-line especially in children.

Sneezing, rhinorrhea:

First-generation antihistamines (e.g. Chlorphenamine, Diphenhydramine) can be useful in controlling runny nose due to their anticholinergic properties. Non-drowsy antihistamines (e.g. Loratadine) are also effective especially when allergy is the underlying cause

Fever, headache, sore throat:

Analgesics (e.g. Paracetamol, Ibuprofen) are generally useful.

Non-drug measures namely increased fluid intake and rest can be beneficial in most cases of cough and cold.

Therapeutic classification of compound cough & cold preparations available in Nigeria

See EMDEX Mobile App for the proprietary preparations

Analgesic-containing preparations

Analgesic with Antihistamine

• Paracetamol + Cetirizine
• Paracetamol + Chlorphenamine
• Paracetamol + Diphenhydramine

Analgesic with Antihistamine & Antitussive

• Paracetamol + Loratadine + Dextromethorphan
• Paracetamol + Doxylamine + Dextromethorphan

Analgesic with Antihistamine & Expectorant

• Paracetamol + Chlorphenamine + Ammonium chloride + Sodium citrate

Analgesic with Antihistamine & Vitamin C

• Paracetamol + Chlorphenamine + Ascorbic acid

Analgesic with Decongestant & Antihistamine

• Paracetamol + Phenylephrine + Chlorphenamine
• Paracetamol + Caffeine + Phenylephrine + Chlorphenamine
• Paracetamol + Caffeine + Phenylephrine + Pheniramine
• Paracetamol + Pseudoephedrine + Chlorphenamine
• Paracetamol + Caffeine + Pseudoephedrine + Chlorphenamine
• Paracetamol + Pseudoephedrine + Triprolidine

Analgesic with Decongestant & Antitussive

• Paracetamol + Phenylephrine + Dextromethorphan
• Paracetamol + Pseudoephedrine + Dextromethorphan

Analgesic with Decongestant, Antihistamine & Vitamin C

• Paracetamol + Caffeine + Phenylephrine + Chlorphenamine + Ascorbic acid

Analgesic with Decongestant, Antihistamine & Expectorant

• Paracetamol + Pseudoephedrine + Chlorphenamine + Ammonium chloride

Analgesic with Decongestant, Antihistamine & Antitussive

• Paracetamol + Pseudoephedrine + Chlorphenamine + Dextromethorphan

Compound decongestant preparations

See analgesic-containing preparations above.

Decongestant with Antihistamine

• Phenylephrine + Chlorphenamine
• Pseudoephedrine + Chlorphenamine

Decongestant with Antihistamine & Antitussive

• Pseudoephedrine + Chlorphenamine + Dextromethorphan
• Phenylephrine + Chlorphenamine + Dextromethorphan
• Ephedrine + Promethazine + Codeine

Decongestant with Antihistamine & Expectorant

• Ephedrine + Chlorphenamine + Ammonium chloride + Sodium citrate + Menthol
• Ephedrine + Diphenhydramine + Ammonium chloride + Sodium citrate + Menthol
• Ephedrine + Cetirizine + Ammonium chloride + Sodium citrate
• Ephedrine + Cetirizine + Ammonium chloride + Sodium citrate + Menthol
• Ephedrine + Chlorphenamine + Ammonium chloride + Sodium citrate

Decongestant with Antihistamine, Antitussive & Expectorant

• Phenylephrine + Chlorphenamine + Dextromethorphan + Guaifenesin
• Pseudoephedrine + Triprolidine + Codeine + Potassium guaiacolsulfonate

Compound antihistamine preparations

See analgesic- and decongestant-containing preparations above

Antihistamine with Expectorant

• Diphenhydramine + Ammonium chloride + Ammonium bicarbonate
• Diphenhydramine + Ammonium chloride
• Diphenhydramine + Sodium citrate
• Chlorphenamine + Ammonium chloride + Sodium citrate
• Chlorpheniramine + Ammonium chloride + Sodium citrate + Guaifenesin
• Chlorphenamine + Ammonium chloride + Sodium citrate + Ipecacuanha
• Chlorphenamine + Ammonium chloride + Sodium citrate + Ipecacuanha + Menthol
• Diphenhydramine + Ammonium chloride + Sodium citrate + Menthol
• Diphenhydramine + Ammonium chloride + Menthol
• Diphenhydramine + Sodium citrate + Menthol
• Diphenhydramine + Sodium citrate + Menthol + Tolu
• Chlorphenamine + Ammonium chloride + Sodium citrate + Menthol
• Chlorphenamine + Sodium citrate + Menthol

Antihistamine with Antitussive

• Chlorphenamine + Dextromethorphan
• Promethazine + Pholcodeine

Antihistamine with Antitussive & Expectorant

• Chlorphenamine + Dextromethorphan + Guaifenesin
• Diphenhydramine + Codeine + Sodium citrate + Menthol
• Diphenhydramine + Codeine + Ammonium chloride + Sodium citrate + Menthol
• Diphenhydramine + Codeine + Ammonium chloride + Menthol

Antihistamine with Menthol

• Diphenhydramine + Menthol
• Cetirizine + Menthol

Compound mucolytic/expectorant preparations

See also above for preparations containing analgesic, decongestant or antihistamine

Antitussive with Expectorant

• Dextromethorphan + Guaifenesin

Expectorants with Demulcents

• Thyme + Primula
• Squill oxymel + Ipecacuanha
• Ammonium chloride + Ipecacuanha + Liquorice
• Ammonium chloride + Ipecacuanha + Liquorice + Peppermint oil
• Ipecacuanha + Honey + Glycerol
• Ammonium chloride + Sodium citrate + Squill + Menthol
• Sodium citrate + Ipecacuanha + Squill oxymel + Anise water + Menthol
• Ipecacuanha + Citric acid + Honey + Glycerol

Mucolytic with Antibiotic

• Bromhexine + Co-trimoxazole

Mucolytic with Antihistamine

• Carbocisteine + Promethazine

Mucolytic with Antihistamine & Expectorant

• Bromhexine + Diphenhydramine + Ammonium chloride + Menthol

Mucolytic with Antitussive & Expectorant

• Bromhexine + Dextromethorphan + Ammonium chloride + Menthol

Mucolytic with Expectorant & Bronchodilator

• Bromhexine + Guaifenesin + Salbutamol
• Bromhexine + Guaifenesin + Salbutamol + Menthol
• Bromhexine + Guaifenesin + Terbutaline + Menthol
• Ambroxol + Guaifenesin + Salbutamol + Menthol

Other compound cough & cold mixtures

Herbal cough & cold remedies

• Thyme + Grindelia + Pimpinella + Primrose + Rose

Glycrrhiza + Terminalia + Zingiber + Curcuma + Mentha