Specialist Forum January 2022

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Vol. 22 • No. 1 • January 2022

Bringing you medical news that matters

FORUM

Oncology | Endocrinology | Dermatology

SPARK THE

1.5 mg/0.5 mL

MOTIVATION FOR CHANGE

IN YOUR TYPE 2 DIABETES PATIENTS Powerful dose from the start without the need to titrate¹

Proven CV benefit in patients with or without established CVD2,3,†

Simple once-weekly dosing in a ready-to-use pen with hidden needle1,4

Better adherence shown in real-world studies vs. other GLP-1 RAs5,6‡

*Trulicity 1.5mg demonstrated statistically superior HbA1C in patients with type 2 diabetes in 8 phase III clinical trials vs metformin, sitagliptin, exenatide BID, insulin glargine, and/or placebo. Trulicity 1.5mg demonstrated noninferior HbA1c reduction vs liraglutide 1.8mg, as well as noninferiority vs insulin glargine in patients with type 2 diabetes and CKD1 Trulicity 1.5mg significantly reduced the risk of MACE-3 (composite of non-fatal MI, non-fatal stroke, or CV death) vs. placebo by 12% on top of standard of care. CV benefit was consistent across subgroups of patients with

†

and without estabalished CVD2,3 ‡

In real-world studies, ~40% more patients with T2DM were adherent to once-weekly Trulicity relative to once-weekly semaglutide, Moreover, persistence with Trulicity was the highest among GLP1 RAs including twice daily

exenatide, once-weekly exenatide, liraglutide and lixisenatide References: 1. Trulicity (dulaglutide once weekly) Trulicity Professional Information, Eli Lilly and Company, Johannesburg, South Africa - 2020. 2. Gerstein HC, et al. Lancet. 2019 ;394:121-130 3. Gerstein HC, et al. Diabetes Obes Metab. 2018;20:42-49 4. Trulicity 1.5mg instructions for use 5. Mody R, et al. Diabetes Obes Metab.2021;23:106-115. 6. Divino V, et al. Diabetes Ther. 2019;10:1067-1088

S4 Trulicity®. Reg No. 51/21.13/0344 Dulaglutide 1,5 mg/ 0,5ml solution for injection. For more product information, please email us at: za_medinfo@lilly.com For full prescribing information, refer to the Professional Information approved by the medicines regulatory authority Eli Lilly (S.A.) (Pty) Ltd. Reg. No. 1957/000371/07 1st Floor, Golden Oak House, Ballyoaks Office Park, 35 Ballyclare Drive, Bryanston, JohannesburgTel: +27 (11) 510 9300 © 2020 Eli Lilly and Company. All Rights Reserved.

PP-DG-ZA-0359

Powerful HbA1c reduction1,*

SF | CONTENTS

CO NT E N TS

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05 11 22 40

4 PRACTICE MANAGEMENT

17

Why it is essential that you keep good medical records

5 ONCOLOGY

11 13 ENDOCRINOLOGY

The evolving metastatic breast cancer landscape

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CPD: IV paracetamol in paediatric patients

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DERMATOLOGY

Acne therapy redesigned

Treating superficial skin infections

Keys to successful diabetes management during Ramadan

EDITORIAL EDITOR: René Bosman René.Bosman@newmedia.co.za

22 PAEDIATRICS

CPD: Contemporary approach to early and advanced breast cancer

Novo Nordisk launches once-weekly semaglutide in South Africa

People with dermatitis at high risk of osteoporosis, major fractures

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Thinking Beyond HbA1c: managing CV risk in patients with T2DM

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Why it is essential that you keep good medical records

Vanessa Rogers,

I

Textbox Conceptual

Many doctors complain that they don’t have sufficient time to keep accurate records, but assuming this attitude, comes at a price. If a patient decides to sue, a lack of appropriate record-keeping will mean the practitioner involved does not have the evidence to back him- or herself up in court.

t’s a familiar scenario – doctors have dozens of people to see in a day and there’s little time for them to record what was wrong with each patient or what course of treatment was decided upon.

Even though doctors know it’s important, record-keeping is frequently given low priority. Notes are often illegible, with information missing and gaps left as to the full treatment protocol.

In some cases, there may even be an inconsistency between what different doctors recorded about the same patient (in the case of referral from one to another or filling in and treating another doctor’s patients during a leave period, for example).

Yet medical records form a fundamental part of patient care. They’re the written record of what diagnosis a patient was given and what medicine was prescribed.

They help other professionals to understand the doctor’s thought process at the time and the diagnostic conclusion they came to. Medical records can be electronic or handwritten and can include lab reports, x-rays, and referrals from other doctors.

According to Indwe Risk Services, when defending a complaint or clinical negligence claim, good medical records can make all the difference.

a necessity. It shows that doctors are taking care of their patients and meeting all their needs. Medical records should be clear, accurate and timely.

They should be made every time a doctor sees their patient and should be kept in chronological order to demonstrate the extent to which the patient is responding to their treatment.

Doctors should make notes as they consult with their patient, or as soon as possible afterwards. It is also possible, especially in the case of illegible handwriting, for a doctor to record their notes on a dictaphone-type device or smartphone, and for an administrative assistant to type these up on a daily or weekly basis.

Another risk advisor, MC de Villiers Brokers, recommends that doctors note in full all decisions made and actions agreed to regarding their patient’s treatment.

Informed consent forms part of this recordkeeping process.

Patients need to be told what options are available to them and what side-effects some medications may deliver. According to South African law, a patient must provide their informed consent to any medical treatment that a doctor proposes.

The importance of accurate and timely medical records

What if a patient sues?

Maintaining good medical records isn’t just

From a legal point of view, it matters little if the doctor did everything right at the

time they treated the patient. If it is not recorded, there is no proof that something was done. This means, in the absence of good medical records, that even the best practitioners may be difficult to defend.

MC De Villiers Brokers advises that doctors bear in mind that the quality of their record-keeping reflects the quality of the care they give their patients. In the case of malpractice allegations, the first thing that an attorney will ask for is the patient’s medical folder, so as to determine whether or not there was negligence.

To safeguard themselves, Indwe Risk Services advises that doctors should make detailed record-keeping an integral part of their daily routine. Doctors should always date and sign their entries and should never alter or edit them.

If they realise later that they’ve made a mistake, they should rather add an amendment. Practitioners should also bear in mind that patients have a right to access their medical records, so nothing offensive or discriminatory should be recorded.

Even with best practice, risks can only be reduced, never removed. By keeping complete, up-to-date, and well-organised medical records, doctors can demonstrate the quality of care that they’ve given to their patients and can more effectively attempt to defend themselves against any legal claims or complaints that are laid against them. SF

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This article was independently sourced by Specialist Forum.

Please note that our CPD activities are

Prof Carol Benn,

only for practitioners

Specialist Surgeon and Head of the Helen Joseph and Netcare Breast Care Centre

registered with the HPCSA. Any other health professional should apply to their own Council for CPD purposes.

Contemporary approach to early and advanced BCa

TECHNICAL TIPS LEARNT THAT MIGHT HELP YOU IN YOUR PRACTICE

The Helen Joseph Hospital (HJH) breast unit provides world-class breast care to the women of Johannesburg, elsewhere in South Africa and women from neighbouring Southern African Development Community countries. Care is delivered in a provincial (government-funded) hospital setting.

P

atient care is excellent and affordable, allowing women (and men) access to all the available methods of diagnosis, breast pathology treatment and counselling through an integrated, education orientated, multicultural navigator multidisciplinary

approach, ensuring cost-effective service delivery and high-quality patient care.

The private-based sister unit hosted at Milpark hospital (The Breast Care Centre of Excellence [BCCE]) offers identical multidisciplinary treatment regimes. This unit is the only internationally accredited unit in

Africa with full accreditation from the National Accreditation Program for Breast Centres.

Holistic care from diagnosis to treatment and survivorship is offered next to the Milpark hospital in an old heritage site hotel.

The unit also provides funding support to the government unit for patient navigators,

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media awareness, and miscellaneous (though often critical consumables) if and when required.

The symbiotic relationship between the HJH government multidisciplinary breast unit and the private sector Netcare Breast Care Centre has proven to be a successful collaborative venture in South Africa and is recognised in neighbouring African states as an example of how a partnership between funded private medical healthcare and nonfunded. This collaborative venture is proof that government services can equate to the highest quality multidisciplinary care for all.

Evolution of BCa treatment Breast cancer (BCa) treatment has evolved over the last 50 years, from a disease treated mainly in the hands of the surgeon to now being a showcase for multidisciplinary team management. Advancement in the understanding of oncological care has resulted in swings from extensive radical surgery (Halstedian mastectomies) to breast conserving treatment (BCT). Greater understanding of tumour biology has seen tremendous strides in the use of oncological drugs and the paradigm shift around understanding cancer spread.

Useful tips _ For every 100 people seen in a breast health practice, only 10% will require surgery _ Whilst history taking is essential, 65% of women diagnosed with BCa have no significant risk factor history _ Whatever the patient arrives with at your unit, review the data _ Work out costs prior to biopsies, and discuss this with your patient _ Should you be practising ‘solo’, you should attach yourself to a multidisciplinary team to ensure safe care. From a professional growth and medico-legal safety, this is essential for all surgeons that are not working in a dedicated breast centre.

Prior to diagnosis

Practice clinical, pathology and radiology review

Clinical assessment _ Pathology before any surgery: there is no role for surgical biopsies as an initial diagnostic tool _ Radiology review in a multidisciplinary meeting: to determine the assessment of needle biopsy accuracy _ Review all pathology and radiology independently: the use of magnetic resonance imaging (MRI) scans and elastography are valuable adjuncts to assess both breasts and regional lymph

nodes to ensure adequate local staging prior to planning treatment.

The HJH breast unit recently incorporated the use of contrast-enhanced mammography (CEM). CEM involves the combined use of an intravenous (IV) iodinated contrast, with an optimal screening window of between two to six minutes post-contrast injection. Postinjection conventional mammogram images are obtained. The entire procedure takes 10 minutes. It allows for a similar assessment of neovascularity as MRI.

Once diagnosed

What is the new standard of care in management?

All patients should be discussed in the following multidisciplinary meetings: _ Clinical radiology meeting: during which correlation between the radiology and the core biopsy pathology should be documented including the need for further investigation _ A multidisciplinary oncology meeting: all treating disciplines (medical oncology, radiation oncology, radiology, pathology, surgical oncology genetics, oncology care physicians, nurse navigation [allied care specialists: lymphoedema, physio, nutritionists]) should be present when the patient is discussed. All decisions around the above meetings should be fed back to the patients with a clear plan of action around treatment.

Each unit should have written documentation of: _ Local treatment guidelines _ Which international guidelines are followed _ Which cases should be discussed that may fall outside of guidelines or require specific non-guideline based treatment choices and why.

If you are not part of a unit, find one that allows you to present your patients online.

This is available through the BCCE with navigation feedback.

The pandemic has resulted in the greater use of online services, including a multidisciplinary meeting, which is beneficial for the practising solo specialists.

Discuss

Delineate 1. Tumour, node, and metastasis (TNM) 2. Biology of BCa 3. Radiological assessment of the breast 4. Mammography (quad, size, microcalcifications, multicentric, multifocality) 5. Ultrasound size and nodal assessment 6. MRI 7. Contrast mammography (new at HJH) 8. Breast size.

Document all information at the start Ensure documentation of the treatment decision pathways, as well as those specific to your patient. All documentation should be circulated and include reasons for the clinical, radiological and treatment decisions.

Management pathway improvements Radiological improvements

Placements of markers have evolved. Postcore biopsy marker placements are critical to delineate areas of either malignancy diagnosis or concern. The rule is that if there is a greater than 4% chance of the area being abnormal, a marker should be placed. Once the marker is placed, should the need for retrieval be required.

Guided localisation at the time of surgery is needed: _ What is historic: skin tattoos to delineate concerning areas _ What is standard: twirl markers and a variety of V markers _ What is new: magnetic markers and wireless markers have long-term placement value. The value of magnetic markers is that surgical margins can also be assessed by determining the distance between the marker and the specimen border.

HJH, Milpark, and Cape Town are involved in the development of a novel long-term, cost-effective marker placement.

Who gets what surgery?

Today there is little reason for a woman not to choose BCT. The absolute oncological indications for a mastectomy today are: _ Inflammatory BCa _ Multicentric BCa. Relative oncological contraindications are: _ Paget’s disease _ Lobular carcinomas _ BCa gene (BRCA) positive.

A woman may elect to have a mastectomy or a bilateral mastectomy, but this is a psychological choice, not an oncological choice (with many reasons being cited): _ Strong family history _ Desire to avoid radiation due to logistics or personal reasons _ Sense of failure in radiology to detect a tumour either due to experience or not wanting future mammograms _ Aesthetic desires involving prosthetic reconstruction.

Before a woman decides on surgery, a detailed discussion explaining the following points must be made: _ Once a BCa diagnosis is made, that cancer determines the outcome, and irrespective of the BRCA or family history, a bilateral mastectomy becomes a choice, not an oncological decision

When their survival could be at risk Uninterrupted activity to give your vulnerable patients more time *

1-5

YULAREB® (Abemaciclib) - A CDK4 & CDK6 inhibitor which can be used as single or combination therapy, indicated for the treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) advanced or metastatic breast cancer 1,6

CLICK HERE for full PI

Disclaimer: Information intended for South African Doctors and Oncology Nurses * Patients with HR+, HER2- advanced breast cancer who progressed after prior ET regardless of menopausal status.

References: 1. PI YULAREB® Approved Professional Information, December 2020. 2. Di Leo A, O’Shaughnessy J, Sledge GW Jr, et al. Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy. NPJ Breast Cancer. 2018;4:41. 3. Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3) [published correction appears in Ann Oncol. 2017;28(12):3111]. Ann Oncol. 2017;28(1):16–33.

4. Dickler M, Tolaney S, Rugo H, et al. MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2— Metastatic Breast Cancer. Clin Cancer Res. 2017;23(17):5218—24. 5. Sledge GW Jr, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy–MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2020;6(1):116-124.

6. Siobhani N, D’Angelo A, Pittacolo M, et al. Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer. Cells 2019;8:321; doi:10.3390/cells804032.

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S4 YULAREB® 200 mg film-coated tablet. Reg. No.: 53/26/0441.437. Each film-coated tablet contains 200 mg abemaciclib.

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_ The survival is equal whether a mastectomy or BCT is performed _ All women should be counselled around the oncology rules _ All women should be discussed in a multidisciplinary meeting _ A clear plan should be presented to the patient before starting treatment _ All women should be offered the opportunity for a second opinion.

BCa treatment does not involve ‘emergency cancer surgery ever’. Breast conservation is not a contraindication in women with big tumours or women with locally advanced BCa, neither in women with metastatic disease. Before discussing different surgical techniques for surgery and reconstruction, let us look at oncology principles that may guide surgery choices:

The axilla _ Are you still doing axillary dissection, and if so, why? Sometimes less is more _ Do you mark your nodes prior to starting primary chemotherapy (ChT)? _ Today the use of sentinel lymph node biopsies for node-negative axilla is the standard. Even in node-positive axillas, post-primary oncology treatment, targeted axillary sampling often replaces the need for an axillary dissection (which is seven lymph nodes).

Oncology discussions Oncology treatment is the umbrella of care.

This means that understanding the biology of BCa as well as the T and N prior to treatment.

The general guidelines are that most triple-negative BCas get primary oncology treatment followed by surgery and radiation (except for a lazy subset of low Ki triple-negative cancers).

Most human epidermal growth factor receptor 2 (HER2) enriched BCa get primary HER2 treatment (either single or dual agent) prior to surgery. In addition, low Ki endocrine sensitive HER2 cancers can now get primary endocrine treatment with HER2 blockade prior to surgery.

Node positive luminal B cancers start with primary ChT, while locally advanced luminal A cancers should start with primary endocrine, and the new kid on the block cyclindependent kinase 4/6 inhibitors. This clever class of drugs shows huge potential with locally advanced endocrine sensitive cancers and metastatic endocrine sensitive cancers.

Early-stage luminal B cancers can start with surgery and sentinel lymph node biopsies followed by genetic profiling, thus avoiding the need for ChT in a subset. Early-stage luminal A cancers can start with primary endocrine therapy or primary surgery.

A subset of luminal A cancers in the elderly can probably avoid surgery and, if the tumours are single and node-negative, have cryo-surgery (freeze the cancers).

Guidelines as to which patients do not require ChT according to genetic profiling must be documented.

The following questions must be addressed during oncological discussions: _ Which advanced patients do not require ChT? For example: extremely low Ki luminal A (low-grade lobular carcinomas), node-positive disease can have primary endocrine treatment (as well as CDK 4/6 inhibitors ) if this has been discussed in a multidisciplinary meeting and authorised by a medical oncologist as the most suitable treatment route _ Which early-stage BCa patients will start with primary ChT? For example: triple negatives, HER2 enriched, high Ki luminal B _ Does your unit use specific ChT regimens for different tumour subtypes? Taxotere, adriamycin and cyclophosphamide for triple negatives _ How does your unit document response to primary ChT (clinically and radiologically)?

• Poor responders to primary ChT are managed by second-line ChT ahead of surgery • Incomplete responders post-ChT and surgery should be offered more oncology treatment options (CREATE for triple negatives) and watch and wait.

What endocrine treatments are offered to what patients and for how long?

Things to consider: _ Do you use extended adjuvant endocrine for all?

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_ Do you offer your young BCa patients an aromatase inhibitor plus gonadotropinreleasing hormone? _ Are gynaecological assessments offered to your patients (they should have yearly assessments and are all young patients who fit criteria for fertility treatment being offered counselling and a fertility assessment.

Radiation All patients should have documentation of the need for radiation with BCT. Discussions should include: _ Whether the patient fits criteria for intraoperative radiation should be assessed according to the American Society for Radiation Oncology guidelines _ Need for radiation due to axillary nodal disease (one or more involved) _ Whether the unit accepts and follows the Z11 protocol for radiation, thus avoiding more axillary surgery, as well as the After Mapping of the Axilla: Radiotherapy Or Surgery (AMAROS) study outcomes _ The pros and cons of hypo-fractionated treatment and whether the patient fits the criteria _ Can radiation possibly be avoided in certain elderly luminal A tumours? _ Availability of intraoperative radiation therapy and use to decrease government load.

Defining oncoplastic surgery Oncoplastic surgery is defined as techniques used at the time of BCT. Whereas this term has been used for many years, it is my opinion that it should be termed onco-reconstructive techniques.

The basis of this surgery is around understanding techniques used during breast plastic surgery, as soon as the word plastic is associated with cancer, there is often an unrealistic patient expectation.

Reconstructive breast surgery is the term used for reconstruction post-mastectomy, be it immediate, immediate-delayed, or delayed.

The first rules

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Breast reconstruction and oncoplastic surgery should be discussed with all patients prior to surgery The vast majority of patients can undergo immediate reconstruction at the time of their cancer surgery (thus avoiding multiple procedures). Many easy techniques that can be learnt and taught to general surgeons Understanding the oncology principles and rules in your unit avoids unnecessary complications around

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reconstruction (such as which patients require radiation) Teamwork in the correct surgical environment enables safe enhanced recovery after surgery principles.

The principles

is reserved for a small subset of patients who have skin loss, particularly in the lower poles.

Prosthetic reconstruction is done once the need for radiation has been accessed and is used in patients requiring radiation with montelukast with good results.

Tumour factors

Autologous reconstruction

_ Understand the size of the tumour _ The position of the tumour _ The radiological and tumour information _ The relationship with nipple-areolar complex _ Distance to skin.

Latissimus flap reconstruction is reserved in the unit in patients presenting with locally advanced BCa post-primary ChT, including in inflammatory BCas. Currently, a technique called the Goldilocks reconstruction has shown to be as effective.

Most of these patients require immediate, delayed reconstruction involving a nipplesparing sometimes and (mostly) skinsparing mastectomy, a 48-hour pathology turn-around on margins (10mm) with margin clearance reconstruction and oncostatin M 48-hours later.

Detailed patient counselling is suggested with a small subset of patients requiring free flaps and strict no time delay to either radiation or ChT being maintained within the unit of a minimum of three weeks and max allowed of six weeks.

Breast factors _ The size of the breast _ The consistency of the breast tissue (fatty breast can be harder to perform oncoplastic techniques if one does not have experience the tissue pulls apart and areas of fat necrosis result from inadequate blood supply _ The degree of ptosis _ Previous breast surgery _ Presence of prostheses (type, size, and age).

Patient factors _ Medical illness that may affect surgery _ Habits such as smoking _ Medication that may affect surgery.

The techniques BCT techniques are two-fold: Volume displacement Involves moving the breast tissue around with types of parenchymal flaps From small rotational flaps to the use of a variety of breast reduction or mastopexy techniques Volume replacement This involves the use of importing locoregional tissue in the vicinity of the BCa excision. In our unit, lateral intercostal artery perforator flaps, thoracoepigastric flaps and regional local flaps are used commonly (with latissimus dorsi flaps reserved for immediate or immediate-delayed medium breast reconstruction in patients post-primary ChT with inflammatory BCa. Other immediate delay alternatives are also available for inflammatory cancers post-primary ChT.

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Mastectomy-based reconstruction Most mastectomies in our unit are skinsparing, with 60% of this being nipple and skin-sparing. This can be either prosthetic or autologous. Prosthetic reconstruction is mainly direct implant reconstruction in our unit without acellular dermal matrixes (ADM).

The use of expander or prosthetic with ADM

The Goldilocks reconstruction Done with a modification of nipple and skinsparing through a lateral type 4 approach with the addition of bilateral thoraco-epigastric flaps is offered in some patients with breast ptosis, and over a C cup breast size.

Special scenarios The unit has a high number of locally advanced patients that are managed, including those with stable or responsive metastatic disease that are offered surgery with reconstruction only after a clear assessment of the value add of surgery after a multidisciplinary team discussion.

A ‘less is more’ approach is taken with metastatic patients requesting some form of reconstructive surgery, with the most conventional techniques being BCT with parenchymal flap reconstructions.

Pregnant BCa patients requiring surgery also are offered local small parenchymal flap reconstruction. Elderly patients are also offered oncoplastic and breast reconstruction as long as anaesthetic safety has been predetermined.

The use of primary endocrine treatment is offered for frail elderly luminal A BCa patients who wish to undergo surgery. The unit is involved in cryo-surgery for a subset of BCa patients.

Survivorship and navigation Allied care

_ Does your unit have radiology and

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oncology navigators helping patients on their cancer journey? _ Do you offer an oncology care physician survivorship programme? _ Are all young BCa patients offered a fertility service and discussion prior to starting treatment? _ What is the unit protocol on which patients are referred for genetic counselling and testing (and when)? _ Which patients are referred for an oncopsychology consult, and when? _ Which patients are referred for lymphoedema physio and when? _ What is the unit policy on complementary oncology care, and how is this managed?

Novel navigation techniques have been adopted at both units. These were conceived at the units involving using trauma coding systems to highlight urgency oncology management needs: _ Colour coded radiology _ Colour coded navigation _ Open access clinic _ Cultural-based navigation.

How has the Covid-19 pandemic affected BCa care?

The upside

More robust virtual multidisciplinary meetings with people having the option to attend these and for these sessions to be recorded. In addition, the value of IT specialists ensuring that all can visualise radiology and pathology slides adds to the concept of multidisciplinary review.

The pandemic has also broadened the horizons of oncology treatment options from more neo-adjuvant (primary) oncology care, more minor safer surgeries, lesser radiation options in terms of treatment.

In the private sector, the pandemic has resulted in a more patient-centred approach (with fewer people rushing into surgery (this is a good thing). More women with early-stage hormone-sensitive BCas were treated with endocrine therapy as a holding treatment prior to surgery (this is a good approach in my opinion as it ensures that women have an opportunity to assess where and what treatments they want).

The good so far: _ A more patient-centred approach _ More virtual and telephonic access to doctors (this should not replace a clinical examination _ Virtual multidisciplinary unit meetings resulting in more doctors accessing interdisciplinary patient decision making _ An international trend to home-based oncology care and safer systems around surgical hospitalisation.

In my unit, due to an inability of visiting

Photo credit: Shutterstock.com

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loved ones, an immediate post-surgery phone call by myself re surgery was instituted (this will be a continued service post-Covid). We set up family Teams or Zoom chats, and this has helped when family is located around the world.

a cancer journey can, like the Comrades, be achieved one small shuffle at a time, so will our getting through this pandemic together.

So a shout out to essential workers and patients … Together we can!

The downside

In conclusion

Significant issues around BCa are always early diagnosis and treatment availability.

The pandemic resulted in fewer women going for their screening mammograms (many women did not screen last year).

Whilst I have not been able to crunch the data yet, more women arrived at HJH breast clinic with advanced cancers. Patient fear of hospitals (general fear around Covid) resulted in non-adherence and late access to care.

Unfortunately, oncology and radiation services for government patients resulted in delays in receiving radiation and some oncology services.

This era of BCa management offers for surgeons dynamic and different treatment options for patients. Therefore, today’s oncology surgeon needs to be trained in all aspects of BCa care, from radiology to radiation. In addition, he/she needs to have comprehensive training in different plastic and reconstructive techniques to recognise which patients for which procedures and to ensure that they work with a team of competent specialists, including plastic/ reconstructive surgeons, so as allow the best patient outcomes for their patients.

The Milpark-based breast centre has pioneered immediate breast reconstruction, multidisciplinary meetings, cancer navigation and survivorship care and received awards for personalised oncology care. The centre is also involved in innovations in cancer care from intraoperative radiation to cryo-surgery. The HJH sister unit has allowed us to ‘bring Africa to the world’ with excellence in cancer care.

References available on request. SF

Effect on patients Some people who are anxious have heightened fears around cancer and Covid, whilst others have many other concerns from financial to dealing with the loss of family members that cancer risks are considered less important. _ Access to care and financial concerns: I have enjoyed running two units and ensuring that all women, irrespective of funding, can access care _ Fear: this is now heightened with Covid.

The importance of support and this is where navigation has been so critical and time (take time with decisions, don’t rush into emergency surgery – there is no such thing). Family and friends and having someone to hold a hand and give a hug (the power of a good hug, is something sorely missed) However, like

To com plete the quiz , go t o w w w . medicala cademic .c o.za and clic k on t h e CPD ta b

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SF | WEBINAR SF | WEBINAR REPORT This article was independently sourced by Specialist Forum.

The evolving metastatic breast cancer landscape

Dr Devan Moodley, medical oncologist and researcher, based at the Wits Donald Gordon Medical Centre in Johannesburg, presented a CPD accredited webinar on advances in breast cancer (BCa) management. The webinar was sponsored

by Eli Lilly and hosted by Specialist Forum.

Content intended for South African doctors and nurses

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PP-AL-ZA-0147

Ca is the most frequently diagnosed cancer in women (29% of all cancer cases). It is the leading cause of cancer death in women worldwide (6.9% of cancer deaths).1 It is estimated that 45% of new cases diagnosed each year, and more than 55% of BCa related deaths, occur in low- and middle income countries. Overall, 30% of patients diagnosed with early BCa will develop recurrent and/or metastatic disease.2,3 Metastatic BCa is incurable and therapeutic goals are most often palliative. Managing symptoms to maintain optimum quality of life (QoL) is a major goal of treatment.4,5 About 70% of the metastatic BCa patient population have hormone receptor positive (HR+) disease. Endocrine therapy (ET) is generally the preferred option for HR+ BCa irrespective of human epidermal growth factor receptor 2 negative (HER2−) status, unless there is evidence of visceral crisis, or concern/proof of endocrine resistance.6,7 Up to 50% of patients with metastatic ER+ BCa exhibit de novo resistance to first-line ET. The rest will eventually relapse due to acquired resistance.12 In the metastatic setting, ET resistance is defined as progression of disease within the first six months of first-line ET for metastatic BCa, while on ET.7,8 New guidelines recommend a CDK4/6 inhibitor combined with ET as the standard of care for all patients with ER+/HER2metastatic BCa. CDK4/6 inhibitors have been shown to improve progression free survival (PFS), and either maintains or improves QoL. Overall survival (OS) results are still awaited.7 Abemaciclib is 14 times more potent against CDK4/cyclin D1 than CDK6/cyclin D3 in enzymatic assays. Numerous studies have investigated the safety and efficacy of abemaciclib in the metastatic setting.6,8,9, A Study of Abemaciclib (LY2835219) In Participants With Previously Treated Breast Cancer That Has Spread (MONARCH 1) evaluated the single-agent activity of abemaciclib in women with refractory HR+/ HER2- metastatic BCa. At the 12 month final analysis, the primary objective of confirmed overall response rate (ORR) was 19.7%, the clinical benefit rate was 42.4%, median PFS was six months, and median OS was 17.7 months.8 The Abemaciclib in Combination With Fulvestrant in Women With HR+/ S4 Yulareb 50 mg. Reg. No.: 53/26/0438.434. Each film-coated tablet contains 50 mg abemaciclib.

S4 Yulareb 100 mg. Reg. No.: 53/26/0439.435. Each film-coated tablet contains 100 mg abemaciclib.

S4 Yulareb 150 mg. Reg. No.: 53/26/0440.436. Each film-coated tablet contains 150 mg abemaciclib.

S4 Yulareb 200 mg. Reg. No.: 53/26/0441.437. Each film-coated tablet contains 200 mg abemaciclib.

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HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy (MONARCH 2) found that abemaciclib plus fulvestrant significantly extended PFS, versus fulvestrant alone (16.4 versus 9.3 months). In patients with measurable disease, abemaciclib plus fulvestrant achieved an ORR of 48.1% compared with 21.3% in the control arm.6 Abemaciclib as Initial Therapy for Advanced Breast Cancer (MONARCH 3) was a phase III study comparing the efficacy and safety of abemaciclib or placebo plus a nonsteroidal aromatase inhibitors (AI) in 493 postmenopausal women with HR+/ HER2advanced BCa who had no prior systemic therapy in the advanced setting. In patients with measurable disease, the ORR was 59% in the abemaciclib and 44% in the placebo arm.10

_ In combination with an AI as initial ET-based treatment in postmenopausal women _ In combination with fulvestrant in women with disease progression following ET. In pre- or perimenopausal women, ET should be combined with a LHRH agonist _ As monotherapy for the treatment of postmenopausal women with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

References 1. Siegel RL, Miller KD, and Jemal A. Cancer statistics, 2020. CA, 2020.

2. O’Shaugnessy J. Extending survival with chemotherapy in metastatic breast cancer.

Oncologist 2005;10(Suppl 3):20-9.

3. Tfayli A, et al. Breast Cancer in Low- and MiddleIncome Countries: An Emerging and Challenging

Up to 50% of patients with metastatic ER+ BCa exhibit de novo resistance to firstline ET

Epidemic. J Oncol, 2010:490631.

4. Roché H and Vahdat LT. Treatment of metastatic breast cancer: second line and beyond. Ann Oncol 2011;22:1000-10.

5. Irvin W, et al. Symptom Management in Metastatic Breast Cancer. Oncologist 2011;16:1203-14.

6. Sledge GW, Toi M , Neven P, et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol, 2017.

7. Cardoso F, Costa A, Senkus E, et al. 3rd ESOESMO International Consensus Guidelines for

A Randomized Study of Abemaciclib as Initial Therapy for Advanced Breast Cancer (MONARCH 3) analysed final PFS data and updated the secondary endpoints of the 2017 MONARCH 3 study. The ABEMACICLIB arm had a significantly longer median PFS than the placebo arm (28.18 versus 14.76 months).

The ORR was 61.0% in the abemaciclib arm versus 45.5% in the placebo arm. The median duration of response was longer in the abemaciclib arm (27.39 months) compared to the placebo arm (17.46 months). The safety profile was consistent with previous reports.

The most frequent AEs in the abemaciclib versus placebo arms were neutropenia, diarrhoea and leukopenia.11

Advanced Breast Cancer (ABC 3). Ann Oncol, 2017.

8. Dickler MN, Tolaney SM, Rugo HS, et al.

MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR +/HER2 – Metastatic Breast Cancer. Clin Cancer Res, 2017.

9. Lallena MJ, Boehnke K, Torres R, et al. Abstract 3101: In-vitro characterization of Abemaciclib pharmacology in ER+ breast cancer cell lines.

Cancer Res, 2015;75(15 suppl):3101.

10. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol, 2017.

11. Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of Abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer, 2019.

Indications in South Africa In South Africa, abemaciclib is indicated for the treatment of HR+/HER2− advanced or metastatic BCa:

12. Global Cancer Statistics 2020: Sung H, Ferlay J, Siegel RL. GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA, 2021..

Eli Lilly (S.A) (Pty) Ltd. Reg. No.: 1957/000371/07. 1st Floor, Golden Oaks House, Ballyoaks Office Park, 35 Ballyclare Drive, Bryanston, 2191. Tel.: +27 11 510 9300.

For full prescribing information, refer to the Professional Information approved by the medicines regulatory authority (12/2020). © 2021 Eli Lilly and Company. All Rights Reserved.

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Keys to successful diabetes management during Ramadan More than a billion Muslims with diabetes worldwide may choose to fast during Ramadan of which about 10% will develop complications2,3 Ramadan is observed by Muslims worldwide as a month of fasting, prayer, reflection, and community. In 2022 the Holy month of Ramadan starts on the evening of 2 April, lasting 30 days and ending at sundown on 1 May.1

T

he duration of daily fasting ranges from a few hours up to 20 hours, depending on the geographical location and season. Apart from fasting (including drinking), Muslims are also expected to abstain from using oral medications and smoking from predawn to after sunset.1 There are no restrictions on food or fluid intake between sunset and dawn. Most people consume two meals per day during this month, one after sunset, referred to in Arabic as Iftar (breaking of the fast meal), and the other before dawn, referred to as Suhur (predawn).1 Fasting during Ramadan is an obligation for all adult Muslims. However, the Koran specifically exempts the sick from fasting – especially if it might lead to harmful consequences for the individual.

Although patients with diabetes fall under this category because of their chronic disorder, many insist on fasting during Ramadan, creating a medical challenge for themselves and their physicians.

It is therefore important that medical professionals are aware of potential risks that may be associated with fasting during Ramadan, and how to manage them.1

Potential risks associated with fasting during Ramadan Patients with diabetes are at risk of major potential complications associated with fasting. These include:1,2,3

Hypoglycaemia Decreased food intake is a well-known risk factor for the development of hypoglycaemia. The Epidemiology of

Diabetes and Ramadan 1422/2001 (EPIDIAR) study showed that fasting during Ramadan increased the risk of severe hypoglycaemia (defined as requiring hospitalisation) some 4.7-fold in patients with type 1 diabetes (T1DM) and ∼7.5-fold in patients with type 2 diabetes (T2DM).2

Hyperglycaemia Long-term morbidity and mortality studies in people with diabetes, such as the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study, demonstrated the link between hyperglycaemia, microvascular complications, and possibly macrovascular complications.1 The extensive EPIDIAR study showed a ∼5-fold increase in the incidence of severe hyperglycaemia (requiring hospitalisation)

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during Ramadan in patients with T2DM and about a ∼3-fold increase in the incidence of severe hyperglycaemia with or without ketoacidosis in patients with T1DM. 2 Diabetic ketoacidosis is a serious complication of diabetes that can be life-threatening. However, new evidence suggests that the risk of diabetic ketoacidosis is not increased during Ramadan fasting. 3

Dehydration and thrombosis Prolonged limitation of fluid intake is a wellknown cause of dehydration. Combined with hyperglycaemia it can result in osmotic diuresis ( inhibition of reabsorption of water and sodium) and contribute to volume and electrolyte depletion.1 Some patients may experience orthostatic hypotension, resulting in dizziness, light headedness, blurred vision, weakness, fatigue, nausea, palpitations and headache. Patients with pre-existing autonomic neuropathy are particularly at risk. Syncope, falls, injuries and bone fractures may result from hypovolemia and the associated hypotension.1 In addition, contraction of the intravascular space can contribute to a hypercoagulable state due to an increase in

clotting factors, a decrease in endogenous anticoagulants, and impaired fibrinolysis.1 The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) emphasise the importance of patient factors and comorbidities when choosing diabetes medications including the presence of comorbidities, atherosclerotic cardiovascular disease, heart failure, chronic kidney disease, hypoglycaemia risk, weight issues and costs.4 According to Ibrahim et al, the key to successful diabetes management in Ramadan should be no different and the general aim is the control of symptoms, prevention of deterioration in glycaemic control and acute complications.4 It is important to inform patients that blood glucose testing during Ramadan does not break the fast – a common misconception in some parts of the world. Blood glucose should be regularly monitored during fasting, especially those on insulin or insulin secretagogues.4 All patients should be educated about the symptoms of hypoglycaemia, and to stop the fast in case of symptoms of hypoglycaemia, hyperglycaemia, dehydration, or acute illness occur and

blood glucose level of <3.9 mmol/L or >16.6 mmol/L.4 Use of self-monitoring of blood glucose should be individualised during Ramadan with need for more frequent monitoring in those at higher risk of hypoglycaemia, especially in regions with longer fasting hours or warmer climate.4

Managing patients during Ramadan Medical nutrition

Medical nutrition therapy should be provided by a registered dietitian or nutrition professional and should include principles of healthy eating behaviours, preventive methods for hypoglycaemia, and proper portion intake.4 Since foods consumed during Ramadan tend to be higher in carbohydrate, strategies should include portion control as well as the possible incorporation of physical activity after meal. The Diabetes and Ramadan International Alliance has developed the Ramadan Nutrition Plan, a web-based tool designed to help HCPs in delivering patient-specific nutrition education for Ramadan.4,5

Physical activity and Taraweeh prayers Although increased physical activity should generally be encouraged in all patients with T2DM, it has to be approached with caution during Ramadan. The Taraweeh prayer during Ramadan after Iftaar meal involves repeated cycles of rising, kneeling, and bowing and should be considered as part of daily exercise. Physical activity should be encouraged for people with diabetes and normal levels may be maintained during the month of Ramadan. However, excessive physical activity may lead to a higher risk of hypoglycaemia and should be avoided, especially before the sunset meal, in those with high risk of hypoglycaemia and those on insulin or insulin secretagogues.4 It is recommended that decision to start a new glucose-lowering medication should be made in advance of start of Ramadan and dose adjustments or medication reviews are done accordingly, especially if hypoglycaemia or tolerability becomes a concern during fasting.4 A key recommendation by the ADA and EASD is the introduction of combination therapy including metformin in newly diagnosed patients. Ibrahim et al recommend against starting patients on a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as a new medication during or immediately prior to Ramadan. Patients should be well established on these drugs prior to start of Ramadan.4

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In addition, caution Ibrahim et al, elderly patients, those with renal impairment, hypotensive patients, or those on diuretics if they are planning to fast for Ramadan, should proceed with caution and consider stopping or reducing the dose of the SGLT2i.4

Injectables It is very important that patients requiring injectable therapy (either a glucagon-like peptide-1 receptor agonist [GLP-1RA] or insulin) are well established on stable injectable therapy preferably for at least four weeks prior to start of Ramadan.4 The efficacy and safety of insulin is dependent on its appropriate use during Ramadan including patient training and education, diet and activity, dose titration, timing (Suhoor and Iftaar) and type of insulin used.4 The ADA and EASD recommend the addition of a GLP-1RA prior to insulin as a first-line injectable therapy if HbA1c is above target despite dual or triple oral therapy. In addition, initial combination of GLP-1RA plus insulin is recommended if HbA1c is >10% and/or >2% above target.4 Depending on the formulation used, the GLP-1RA may need to be injected daily or once-weekly. Weekly preparations are an attractive option for fasting patients who prefer a simplified regimen.4 The most common adverse events (AEs) of GLP-1RA are gastrointestinal effects including nausea and vomiting, increasing the risk of dehydration. Thus, it is recommended that GLP-1RA should be started at least four to eight weeks prior to fasting with titration to tolerated dose before the start of Ramadan.4 Two recent real-world studies look at the safety and efficacy of insulin glargine 300U/mL (GLA-300) and iGlarLixi, a once-daily fixed-ratio combination of basal insulin glargine and lixisenatide (a GLP-1RA) in patients with T2DM who fast during Ramadan.6,7

The ORION study The ORION study by Hassanein et al (2020) evaluated the safety and effectiveness of Gla-300 in insulin-treated people with T2DM before, during and after Ramadan, in a real-world setting.6 This prospective, observational study across 11 countries included participants with T2DM treated with Gla-300 in preRamadan, Ramadan, and post-Ramadan periods. The primary endpoint was the percentage of participants experiencing ≥1 event of severe and/or symptomatic documented hypoglycaemia with selfmonitored plasma glucose (SMPG)

3.9mmol/L during Ramadan. Secondary endpoints included change in HbA1c and insulin dose and AEs.6 The mean ± SD number of fasting days was 30.1 ± 3.2. The percentage of participants experiencing ≥1 event of severe and/or symptomatic documented hypoglycaemia (SMPG ≤7%) was low in the pre-Ramadan (2.2%), Ramadan (2.6%) and post-Ramadan (0.2%) periods.6 No participants reported severe hypoglycaemia during Ramadan or postRamadan. One participant reported severe hypoglycaemia in pre-Ramadan. HbA1c fell pre- to post-Ramadan, and Gla-300 daily dose (mean ± SD) was reduced preRamadan to Ramadan (from 25.6 ± 11.9 U/0.32 ± 0.14U/kg to 24.4 ± 11.5U/0.30 ± 0.13U/kg). Incidence of AEs was 5.5%.6

hypoglycaemia (plasma glucose [PG] 3.9mmol/L, primary endpoint) was 1.3% during pre-Ramadan, 2.0% during Ramadan, and none during post-Ramadan.7 No participant reported hypoglycaemia with PG <3mmol/L and there were no severe or serious hypoglycaemia events.

The rate of severe and/or symptomatic documented hypoglycaemia (PG ≤3.9mmol/L) was 0.02 per patient-month.7 Improvements were observed for mean ±SD HbA1c and fasting PG (pre-Ramadan, 8.4±1.1% and 146.9±32.1mg/dL to postRamadan, 7.5±0.8% and 122.5±28.8mg/dL) with an average reduction of -0.8±1.1% and -24.4±32.6 mg/dL, respectively. AEs were low (5.8%) and were not considered related to iGlarLixi, and there were no serious AEs.7

The SOLIRAM study

Conclusions

The SOLIRAM study by Hassanein et al (2021), which will be conducted in two waves, evaluated the real-World safety and efficacy of iGlarLixi in patients with T2DM.7 In wave 1 of the study, adults with T2DM who had taken iGlarLixi for ≥3 months before inclusion and who planned to fast for ≥15 days during Ramadan, were enrolled from five countries. During the study, iGlarLixi treatment was adjusted as per routine practice by the treating physician.7 Overall, 155 people with T2DM (54.2% male) were eligible. Mean ±SD age was 58.4±9.5 years, body mass index was 30.5±6.0kg/m² and 64.5% of people had ≥1 diabetes-related complications. 7 Proportion of patients with ≥1 macroand microvascular complications were 11.0% and 48.4%, respectively. Mean ±SD duration of diabetes was 14.0±6.6 years and duration of iGlarLixi treatment prior to study participation was 5.7±3.3 months.7 Mean ±SD length of fasting was 28.7±3.3 days and only 5.9% broke the fast during Ramadan. Reported reasons for breaking the fast were travel, pre-existing conditions, AEs (not related to iGlarLixi), hypoglycaemia, and menses.7 Change in anti-hyperglycaemic treatment class was minimal during the study with 79.4% and 54.2% of people taking biguanides and sulfonylureas during Ramadan, respectively.7 The mean ±SD iGlarLixi dose changed from 24.8±11.6U (pre-Ramadan) to 23.8±10.5U (Ramadan period) and 24.9±11.6U (post-Ramadan). During Ramadan, 89.5% and 7.2% of people took iGlarLixi at Iftar and before Suhur, respectively.7 The number of participants reporting ≥1 severe and/or symptomatic documented

In the ORION study, people with T2DM treated with Gla-300 who fasted during Ramadan had a low risk of severe/ symptomatic hypoglycaemia and improved glycaemic control.6 In the SOLIRAM study, people with T2D treated with fixed-ratio combination, iGlarLixi, were able to fast for most of the month of Ramadan. The incidence of hypoglycaemia was low and glycaemic control was improved.7

References 1. Al-Arouj M, Bouguerra R, Buse J, et al.

Recommendations for Management of Diabetes During Ramadan. Diabetes Care, 2005.

2. Salti I, Benard E, Detournay B, et al. A Population-Based Study of Diabetes and Its Characteristics During the Fasting Month of Ramadan in 13 Countries. Diabetes Care, 2004.

3. Beshyah SA, Chowdhury TA, Ghouri N, et al. Risk of diabetic ketoacidosis during Ramadan fasting: a critical reappraisal. Diabetes Res Clin Pract 2019.

4. Ibrahim M, Davies MJ, Ahmad E, et al.

Recommendations for management of diabetes during Ramadan: update 2020, applying the principles of the ADA/EASD consensus. BMJ Open Diabetes Res Care, 2020.

5. Handy O, Yusof BNM, Reda WH, et al. Chapter 7: the Ramadan nutrition plan (RNP) for patients with diabetes, 2016. Available: http://www. daralliance.org/daralliance/ 6. Hassanein M, Buyukbese MA, Malek R, et al. Realworld safety, and effectiveness of insulin glargine 300 U/mL in participants with type 2 diabetes who fast during Ramadan: The observational ORION study. Diabetes Res Clin Pract, 2020.

7. Hassanein M, Sahay RK, Malek R, et al. RealWorld Safety and Effectiveness of iGlarLixi in People With Type 2 Diabetes who Fast During Ramadan: Results From Wave 1 of the SOLIRAM Study. J Endocr Soc, 2021. SF

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Novo Nordisk launches once-weekly semaglutide in South Africa Once-weekly semaglutide, a human glucagon-like peptide 1 receptor agonist (GLP1‑RA), was launched in South Africa on 21 August 2021. Semaglutide provides superior and clinically meaningful reductions in blood glucose and weight, in addition to proven cardiovascular (CV) benefits in people living with type 2 diabetes (T2DM).1-7

A

ccording to the 9th edition of the International Diabetes Foundation (2019), an estimated 463 million people globally have diabetes (type 1 and T2DM combined).

T2DM accounts for the vast majority (around 90%) of cases.8,9 The number of people living with T2DM is projected to increase to 700 million in 2045. The greatest increase will be seen in Africa. In 2017, an estimated 16 million South African adults (>25-years) were living with T2DM, of which 69% were unaware of their status.1 Dr Zaheer Bayat, head of the Department of Endocrinology at Helen Joseph Hospital in Johannesburg, said the main reasons why so many South Africans remain undiagnosed are:1 Patients are hesitant to get tested Lack of access to healthcare (many live far from hospitals and clinics) Denial (do not want to accept diagnosis)

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Availability of therapies in the public versus the private sector.

The situation is not unique to South Africa, noted Dr Bayat. Similar scenarios are prevalent in other African countries as well as the Middle East. Education and awareness about the diagnosis of T2DM and the availability of effective treatments are needed to overcome these challenges.1

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Keynote speaker presentations A number of international and local experts presented at the launch of semaglutide.

This article summarises some of the presentations.

Incretin-based therapies: How do they work?

Dr Daniel Drucker, LunenfeldTanenbaum Research Institute, Mount Sinai Hospital, University of Toronto (Canada) The first incretin hormone, glucosedependent insulinotropic polypeptide,

was isolated in the 1970s. In 1985 a GLP-1, GLP-1 amide was characterised and was shown to have insulinotropic properties. In 1987 the GLP-1 sequence was discovered. This discovery revealed that GLP-1 was an insulin-stimulating glucoregulatory hormone.10 In 1993, researchers demonstrated that in patients with poorly controlled T2DM, a single exogenous infusion of GLP-1 increased insulin levels in a glucosedependent manner.10 It has subsequently been recognised that GLP-1 is degraded by the ubiquitous protease dipeptidyl peptidase-4 (DPP-4), and thus that GLP-1 not only stimulates glucose-mediated insulin secretion but also has inhibitory effects on glucagon secretion, gastric emptying, and enhancing satiety, facilitating weight loss.10 Pivotal studies in patients with T2DM resulted in the approval of the first GLP1RA in 2005. Today, multiple GLP-1RAs are approved for the treatment of T2DM.10 Once-weekly semaglutide was

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approved by the American Food and Drug Administration in 2017 as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM.11 In 2021, semaglutide was approved for chronic weight management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure, T2DM, or high cholesterol), for use in addition to a reduced calorie diet and increased physical activity.12

CV benefit of GLP-1RAs Subsequent research led to the discovery that GLP-1RAs have cardiovascular (CV) benefit, said Dr Drucker.1 Scott et al investigated the association of variants in six genes that encode drug targets for obesity or T2DM with a range of metabolic traits.13 They compared associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials and tested the association of those variants with disease outcomes, including coronary heart disease, in order to predict the CV safety of GLP-1RAs. They found that a low-frequency missense variant in the gene encoding GLP1 (the target of GLP1RA) was associated with lower fasting glucose and lower T2DM risk. The minor allele was also associated with protection against CV diseases, thus providing evidence that GLP1RA are not likely to be associated with an unacceptable increase in CV risk.13

All-cause mortality Dr Drucker pointed out that it is important to not only look at the CV benefits of this class of drug, but also on overall health.

GLP-1RAs have been shown to reduce the risk of all-cause mortality1 as shown in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. The LEADER trial showed GLP1-RAs decrease the rate of the first occurrence of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke among patients with T2DM compared to placebo.6 About a decade ago, concerns were raised about an increased risk of pancreatitis and pancreatic cancer with the use of GLP-1RAs. Subsequently, realworld data show that GLP-1RAs are not associated with an increased risk, said Dr Drucker.1 El Aziz et al performed a meta-analysis of cases of acute pancreatitis and pancreatic cancer as well as any malignant neoplasm reported in CV outcomes trials (CVOTs) with GLP-1RAs and DPP-4

inhibitors. Individual CVOT data of GLP1RA indicated a significantly elevated risk of acute pancreatitis, pancreatic cancer, or malignant neoplasms. However, a 75% risk increase for the development of an acute pancreatitis was seen in the meta-analysis of DPP-4 inhibitor CVOTs.14

Subgroups that benefit from GLP-1RAs In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) trial, a post-hoc analysis assessed the CV protective effects of semaglutide in various patient populations (gender, age, and baseline CV risk). The researchers found that once-weekly semaglutide versus placebo reduced the risk of major adverse cardiovascular events in all participants regardless of gender, age, or baseline CV risk profile.15

Efficacy of short- versus long-acting GLP1-RAs The Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial found that semaglutide was superior to exenatide extended release in improving glycaemic control and reducing weight after 56 weeks of treatment.

These results indicate that semaglutide treatment is highly effective in patients with T2DM inadequately controlled on oral antidiabetic drugs. 3 The Semaglutide versus Dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial found that semaglutide was superior to dulaglutide in improving glycaemic control and reducing body weight, enabling a significantly greater number of patients with T2DM to achieve clinically meaningful glycaemic targets and weight loss.5

SUSTAIN clinical programme Dr Aslam Amod, endocrinologist based in KwaZulu-Natal and co-author of the South African T2DM guideline

The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) clinical trial programme involved more than 20 000 patients globally and comprises 17 phase 3 studies.1 Dr Amod focused on the findings of the following studies:

_ Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial: semaglutide significantly improved HbA1c and weight in patients with T2DM compared with placebo.16 _ Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial: once-weekly semaglutide was superior to sitagliptin at improving glycaemic control and reducing weight in patients on metformin, thiazolidinediones, or both.

Semaglutide seems to be an effective add-on treatment option for this patient population. 2 _ Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulinnaive patients with type 2 diabetes (SUSTAIN 4): a randomised, openlabel, parallel-group, multicentre, multinational, phase 3a trial: compared with insulin glargine, semaglutide resulted in greater reductions in HbA1c and weight, with fewer hypoglycaemic episodes, and was well tolerated, with a safety profile similar to that of other GLP-1 receptor agonists.4 _ Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial: Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in patients with uncontrolled T2D vs placebo.17 _ Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a doubleblind, phase 3b, randomised controlled trial: Once-weekly semaglutide 1mg was superior to daily canagliflozin 300mg in reducing HbA1c and weight in patients with T2DM uncontrolled on metformin therapy. These outcomes might guide treatment intensification choices.18 _ Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial: adding semaglutide to Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT-2i) therapy significantly improves glycaemic control and reduces weight

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in patients with inadequately controlled T2DM and is well tolerated.19 _ Efficacy And Safety Of Semaglutide 1.0 mg Once Weekly Versus Liraglutide 1.2 mg Once Daily (SUSTAIN 10): both treatments were effective in reducing HbA1c and weight in patients with T2DM and demonstrated superior efficacy with semaglutide 1mg once weekly compared with liraglutide 1.2mg once daily. These findings are consistent with those from the SUSTAIN 3 and 7 trials (see above).

In conclusion, the SUSTAIN 10 results support semaglutide as a favourable treatment option in clinical practice. 20 _ Efficacy and safety of once-weekly semaglutide 2.0 mg versus 1.0mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial: semaglutide 2mg was superior to 1mg in reducing HbA1c, with additional weight loss and a similar safety profile. This higher dose provides a treatment intensification option for patients with T2DM treated with semaglutide in need of additional glycaemic control. 21

Results across SUSTAIN 1-5 and 7-10 _ Reductions in HbA1c greater with semaglutide than comparators (placebo, sitagliptin, exenatide extended release, insulin glargine, dulaglutide, canagliflozin, liraglutide)2,3,4,5,6,16,17,18,19,20 _ Semaglutide consistently improved glycaemic control, regardless of: • Baseline BMI15 • Background treatment4 • Diabetes duration15 • Age15 • Baseline estimated glomerular filtration rate or pre-existing chronic kidney disease. (Reference unclear in presentation) _ Semaglutide consistently reduced fasting PG and/or PPG suggesting both contribute to significantly better glycaemic control versus comparators2,3,4,5,6,17,18,19,20,21 _ Reductions in HbA1c were greater in patient with higher baseline HbA1c.4,5

Ongoing studies _ A Research Study to Compare Semaglutide to Insulin Aspart, When Taken Together With Metformin and Insulin Glargine, in People With Type 2 Diabetes (SUSTAIN 11): will compare the effect of semaglutide once weekly to insulin aspart three times daily as a add on to metformin and insulin glargine in patients with T2DM. 22 _ A Research Study to See How

Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW): will look at whether semaglutide can slow down the growth and worsening of chronic kidney disease in people with T2DM. 23

Multifactorial and individualised patient-centred care: the art of medicine – Dr Landi Lombard, endocrinologist, and Director of the Cape Town Medical Centre

The art of medicine comprises individualised care that depends on the knowledge and experience of the healthcare professional. The better and more comprehensive his or her knowledge and experience, the easier it will be to individualise the care of patients, said Dr Lombard.1 The aims of diabetes care are to:1 Optimise patient survival by addressing all CV risk factors Control glucose with hypoglycaemia, weight gain or side effects to reduce the risk of diabetes-related complications Improve patients’ quality of life.

Numerous studies have shown an association between the degree of hyperglycaemia and increased risk of microvascular complications, sensory neuropathy, myocardial infarction, stroke, macrovascular mortality, and all-cause mortality in patients with T2DM. 24 The UK prospective diabetes study looked at the effect of intensive control of blood glucose (HbA1c of 7% versus 7.9%).

The study found that each 1% reduction in mean HbA1c was associated with reductions in risk of 21% for any end point related to diabetes, 21% for deaths related to diabetes, 14% for myocardial infarction, and 37% for microvascular complications. 24 The researchers concluded that the risk of diabetic complications was strongly associated with previous episodes of hyperglycaemia. Any reduction in HbA1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA1c values in the normal range (<6%). 24

1

2

3

How do we modify CV risk in T2DM? The effective management of T2DM requires a multifactorial approach, which has been shown to improve patient outcomes.

A multifactorial approach focuses on addressing the different risk factors in patient with T2DM, said Dr Lombard.1

Gaedi et al (2008) evaluated whether intensified multifactorial intervention (tight glucose regulation and the use of reninangiotensin system blockers, aspirin, and lipid-lowering agents) reduces the risk of nonfatal CV disease among patients with T2DM and microalbuminuria. The mean treatment period was 7.8 years and patients were followed observationally for a mean of 5.5 years. The primary endpoint at 13.3 years of follow-up was the time to death from any cause. Intensive therapy was associated with a lower risk of death from CV causes (45%) and of cardiovascular events (42%). 25 In their 21-year old follow-up study, Gaedi et al (2016) studied the potential long-term impact of a 7.8 years intensified, multifactorial intervention in patients with T2DM and microalbuminuria in terms of gained years of life and years free from incident CVD. The patients in the intensivetherapy group survived for a median of 7.9 years longer than the conventional-therapy group patients. Median time before first CV event after randomisation was 8.1 years longer in the intensive-therapy group.

Patients in the intensified group had a 33%-45% decreased risk of microvascular complication, except for peripheral neuropathy, which increased by 12%. 26 Rawshani et al investigated whether the excess risk of death and CV events among patients with T2DM could be reduced or eliminated. They assessed patients with diabetes according to age categories and the presence of five risk factors:27

Elevated glycated haemoglobin level

1

2 3

E levated low-density lipoprotein cholesterol (LDL-C) level

Albuminuria

4

5

Smoking Elevated blood pressure (BP).

Among patients with T2DM, the excess risk of outcomes decreased stepwise for each risk-factor variable within the target range.

Among patients who had all five variables within target ranges, the hazard ratio for death from any cause, as compared with controls, was 1.06, the hazard ratio for acute myocardial infarction (AMI) was 0.84, and the hazard ratio for stroke was 0.95. 27 The risk of hospitalisation for heart failure was consistently higher among patients with diabetes than among controls (hazard ratio 1.45). In patients with T2DM, a glycated haemoglobin level outside the target range was the strongest predictor of stroke and AMI, and smoking was the strongest

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predictor of death. The researchers concluded that patients with T2DM who had five risk-factor variables within the target ranges appeared to have little or no excess risk of death, MI, or stroke, compared to the general population. 27

• In patients at moderate CV risk, aspirin for primary prevention is not recommended.

semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a

1. Novo Nordisk. Ozempic launch, 21 August 2021.

double-blind, randomised, placebo-controlled,

2. Ahrén B, et al. Efficacy and safety of once-weekly

parallel-group, multinational, multicentre phase 3a

add-on to metformin, thiazolidinediones, or both,

Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A

week, double-blind, phase 3a, randomised trial.

Randomized, Controlled Trial. J Clin Endocrinol

Lancet Diabetes Endocrinol, 2017.

Metab, 2018.

3. Ahmann AJ, et al. Efficacy and Safety of Once-

18. Lingvay I, et al. Efficacy and safety of once-weekly

Weekly Semaglutide Versus Exenatide ER in

semaglutide versus daily canagliflozin as add-on

Subjects With Type 2 Diabetes (SUSTAIN 3): A

to metformin in patients with type 2 diabetes

56-Week, Open-Label, Randomized Clinical Trial.

(SUSTAIN 8): a double-blind, phase 3b, randomised

Diabetes Care, 2018.

4. Aroda VR, et al. Efficacy and safety of once-weekly

controlled trial. The Lancet, 2019.

19. Zinman B, et al. Semaglutide once weekly as

semaglutide versus once-daily insulin glargine as

add-on to SGLT-2 inhibitor therapy in type 2

add-on to metformin (with or without sulfonylureas)

diabetes (SUSTAIN 9): a randomised, placebo-

in insulin-naive patients with type 2 diabetes group, multicentre, multinational, phase 3a trial.

Risk factors in patients with T2DM can be modified through:28,29,30 _ Lifestyle modification • Reduce calorie intake to reduce excessive weight • Moderate to vigorous physical activity for more than 150 minutes a week is recommended for the prevention and control of diabetes • Smoking cessation _ Glycaemic target • Appy tight glucose control, targeting a near normal HbA1c (<7%) to decrease microvascular complication. _ BP targets • Target systolic BP to 130mm/Hg and <130mm/Hg if tolerated, but not <120mm/Hg • In older patients (>65 years), the systolic BP target should be between 130-139mm/Hg _ Dyslipidaemia targets • In patients at extremely high CV risk, the recommended LDL-C target is <1.4mmol/L or LDL-C reduction of ≥50% • In patients at high CV risk, the recommended LDL-C target is <1.8mmol/L or LDL-C reduction of ≥50% • In patients at moderate CV risk, the recommended LDL-C target is <2.5mmol/L. _ Platelet target • In patients at high/extremely high CV risk, aspirin may be considered in primary prevention

trial. The Lancet, 2017.

17. Rodbard HW, et al. Semaglutide Added to

in patients with type 2 diabetes (SUSTAIN 2): A 56-

(SUSTAIN 4): A randomised, open-label, parallel-

Targeted prevention strategies to reduce CVD in patients with diabetes and pre-diabetes

Cardiovascular Diabetology, 2019.

16. Sorli C, et al. Efficacy and safety of once-weekly

References

semaglutide versus once-daily sitagliptin as an

Medicine is a science of uncertainty and an art of probability – Sir William Osler, the father of modern medicine

and baseline CV risk profile in the SUSTAIN 6 trial.

Lancet Diabetes Endocrinol, 2017.

5. Pratley RE, et al. Semaglutide once weekly versus

controlled trial. The Lancet, 2019.

20. Capehorn MS, et al. SUSTAIN 10: efficacy and safety of semaglutide 1.0 mg once weekly versus liraglutide 1.2 mg once DAI. EMJ Diabet, 2019.

21. Frias JP, et al. Efficacy and safety of once-weekly

dulaglutide once weekly in patients with type 2

semaglutide 2.0 mg versus 1.0 mg in patients with

diabetes (SUSTAIN 7): a randomised, open-label,

type 2 diabetes (SUSTAIN FORTE): a double-blind,

phase 3b trial. Lancet Diabetes Endocrinol, 2018.

6. Marso SP, et al. Semaglutide and cardiovascular

randomised, phase 3B trial. The Lancet, 2021.

22. US National Library of Medicine. A Research Study

outcomes in patients with type 2 diabetes. N Engl J

to Compare Semaglutide to Insulin Aspart, When

Med. 2016.

Taken Together With Metformin and Insulin Glargine,

7. Ozempic® South Africa PI. 8. Foresight Global Health. Addressing the

in People With Type 2 Diabetes(SUSTAIN 11).

23. US National Library of Medicine. A Research

Unmet Needs of People Living with Diabetes:

Study to See How Semaglutide Works Compared

100 years after the discovery of insulin. https://

to Placebo in People With Type 2 Diabetes and

foresightglobalhealth.com/addressing-the-unmetneeds-of-people-living-with-diabetes-100-yearsafter-the-discovery-of-insulin/.

9. International Diabetes Foundation. IDF Diabetes Atlas, 9th edition. Worldwide toll of diabetes. https:// www.diabetesatlas.org/en/sections/worldwide-tollof-diabetes.html.

10. Drucker DJ, et al. Discovery, characterization, and

Chronic Kidney Disease (FLOW).

24. Stratton IM, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ, 2000.

25. Gaede P, et al. Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes. NEJM, 2008.

26. Gaede P, et al. Years of life gained by multifactorial

clinical development of the glucagon-like peptides.

intervention in patients with type 2 diabetes mellitus

The Journal of Clinical Investigation, 2017.

and microalbuminuria: 21 years follow-up on the

11. FDA. FDA Approves Semaglutide Injection For

Steno-2 randomised trial. Diabetologia, 2016.

the Treatment of Adults with Type 2 Diabetes.

27. Rawhani A, et al. Risk Factors, Mortality, and

Endocrine News, 2017.

12. FDA. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA News Release, 4 June 2021.

13. Scott RA et al. Genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. Sci Transl Med, 2016.

Cardiovascular Outcomes in Patients with Type 2 Diabetes. NEJM, 2018.

28. American Diabetes Association. Standards Of Medical Care In Diabetes -2016. Diabetes Care, 2016.

29. Ross SA. Breaking Down Patient and Physician Barriers to Optimize Glycemic Control in Type 2 Diabetes. The American Journal of Medicine, 2013.

14. El Aziz MA, et al. Incretin-based glucose-lowering

30. Cosentino F. 2019 ESC Guidelines on diabetes,

medications and the risk of acute pancreatitis

pre-diabetes, and cardiovascular diseases

and malignancies: a meta-analysis based on

developed in collaboration with the EASD:

cardiovascular outcomes trials. Diabetes, Obesity

The Task Force for diabetes, pre-diabetes,

and Metabolism, 2019.

and cardiovascular diseases of the European

15. Leiter LA, et al. Cardiovascular risk reduction with

Society of Cardiology (ESC) and the European

once-weekly semaglutide in subjects with type

Association for the Study of Diabetes(EASD).

2 diabetes: a post hoc analysis of gender, age,

European Heart Journal, 2020. SF

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SF | CPD: PAEDIATRICS

January 2022 | Vol. 22 No. 1

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IV paracetamol in paediatric patients Please note that our CPD activities are only for practitioners registered with the HPCSA. Any other health professional should apply to their own Council for CPD purposes.

Intravenous (IV) paracetamol is a drug used widely (more than 80 countries worldwide) with substantial experience and data pertaining to both safety and efficacy as both an analgesic and anti-pyretic.1,2

I

t was approved by the American Food and Drug Administration in 2010 for use in children aged two years and above.1,3

Indications for the use of IV paracetamol The indications for the use of IV paracetamol include: _ Treatment of mild to moderate pain and fever when alternate routes of administration are not possible and/or there is an urgent need for therapy _ Treatment of moderate to severe pain as part of a multimodal approach to analgesia (given its’ opioid sparing properties either as an alternative or supplement) _ When opioids are either contraindicated or there are considerable concerns

Dr Kuban D Naidoo, MBBCh (Wits) DCH(SA) FCPaed(SA) MMed [Paeds](Wits) CertCritCare [Paeds](SA)

surrounding the adverse effects of opioids.1-4 IV paracetamol is prominently indicated for post-operative analgesia and has shown efficacy in reducing postoperative nausea and vomiting when used prophylactically.

Several studies have demonstrated the adequacy of analgesia while demonstrating less sedation and shorter recovery times.3 Despite the proven efficacy of paracetamol as an analgesic the exact mechanism of action remains incompletely understood.

It acts at both central and peripheral components of the pain pathway.2,3 In addition to inhibition of cyclooxygenase enzymes (reduction of prostaglandin production via inhibition of prostaglandin synthase), paracetamol acts on the endogenous opioid, serotoninergic bulbospinal and nitric oxide pathways. 2,3

Senior Paediatric Intensivist, Department of Critical Care, Chris Hani Baragwanath Academic Hospital, Johannesburg

Lastly paracetamol also appears to act on both N-methyl-D-aspartate (NMDA) and cannabinoid CB1 receptors in the brain and spinal cord. 2,3

Rapid onset of action IV paracetamol has a rapid onset of action with analgesic and antipyretic effects within 15 and 30 minutes, respectively. 2,3 The speed of onset of analgesia is due to a rapid time to maximum plasma concentration of 15 minutes as compared to 45 minutes (oral) and three to four hours (rectal). 3 IV paracetamol rapidly crosses the blood-brain barrier achieving higher cerebrospinal fluid (CSF) concentrations and more effective antipyretic effects for the first 60 minutes compared to an equivalent oral dose. Peak analgesic

When it’s critical, Fresenius Kabi has a solution.

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January 2022 | Vol. 22 No. 1 www.medicalacademic.co.za

effects are achieved by one hour and both analgesic and antipyretic effects last up to six hours. 2,3

Safety profile of IV paracetamol The safety profile of IV paracetamol is favourable compared to either nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids. 2 Adverse effects include nausea and vomiting, constipation, pruritis, agitation and atelectasis. 3 Significant adverse reactions are extremely rare (<1/10000) and include the development of asthma, rhinoconjunctivitis and eczema in adolescents.1,2 NB: It is very important to check the dosing regimen of IV paracetamol as it is not the same as the dosing regimen for oral paracetamol and problems have arisen from either the incorrect use of doses recommended for the oral drug and/ or dosing errors where milligrams(mg) are replaced by milliliters(ml).5

Dosing of IV paracetamol The dosing of IV paracetamol in children depends on both age and weight. Infusions of IV paracetamol are given over 15 minutes with a minimum interval of four hours between doses. Table 1 is largely based on the dosing recommendations of the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom (UK).1,3 The MHRA dosing regimen for infants, term and preterm neonates has recently been challenged due to concerns of underdosing. The details of two proposed regimens (based on gestational age) are as follows: A six hourly dosing interval of 10mg/ kg (28-<32 weeks) or 12.5mg/kg (32<36 weeks) or 15mg/kg (≥36 weeks) 6 A loading dose of 20mg/kg followed by 10mg/kg for preterm neonates or 15mg/kg for term neonates and older infants. The dosing interval should be six hourly for neonates/infants born after 31 weeks gestation or 12 hourly for those born between 28 and 31 weeks’ gestation.5

1

2

Pharmacokinetics IV paracetamol is metabolised by the liver predominantly via glucuronidation and sulfation. At higher doses additional metabolism via the cytochrome p450 pathway produces N-acetyl-pbenzoquinone (NAPQI) which rapidly conjugates with glutathione and is excreted in urine.1,2 The majority (90%) of the metabolised drug is excreted in urine within 24 hours with <5% of drug excreted unchanged.

With toxic doses, the excess of NAPQI produced depletes available glutathione resulting in hepatocellular damage by unconjugated NAPQI.1,2 While IV paracetamol remains contraindicated in patients with severe and active liver disease, it is safe to use at recommended doses in patients with mild to moderate liver dysfunction.1,2 There is a greater risk of toxicity in patients predisposed to lower levels of glutathione (chronic malnutrition, severe dehydration) even within recommended dosing limits.1,3 Caution should also be exercised in neonates with unconjugated hyperbilirubinaemia.6 Drug clearance is slower in children younger than two years of age so six hourly dosing intervals is preferable. Furthermore, as a result of delayed clearance due to severe renal dysfunction (creatinine clearance <30ml/min), the minimum dosing interval should be increased from four to six hours. 2 With respect to infusion, IV paracetamol is physically incompatible with both diazepam and chlorpromazine hydrochloride. 3 Lastly, studies in adults have raised concerns of decreased blood pressure upon administration of IV paracetamol.

This has recently been investigated among paediatric patients.

A retrospective chart review of 100 patients found no haemodynamically significant impact following the administration of IV paracetamol.

Decreases in blood pressure were usually

from supra-normal levels to normal levels, due to the relief of pain.7 However, a second study among 45 children with septic shock found a decline in mean arterial pressure of at least 15% following 32.4% of doses which necessitated the administration of either a fluid bolus or increase in inotropic dose after 11.4% of doses.8 The difference in the findings of the two studies are attributable to the different patient populations (only three patients with septic shock in the first study) and the indications for the paracetamol (68% pain in the first study and 79% fever in the septic shock study).

Thus, among haemodynamically unstable children, the administration of IV paracetamol may result in clinically significant hypotension and should be used with caution.

References: 1. Irshad MI, Malik M, Furqan A. Intravenous paracetamol in pediatrics: A global perspective.

Anaesth Pain & Intensive Care. 2012;16(3);311-4.

2. Duggan ST, Scott LJ. Intravenous Paracetamol (Acetaminophen). Drugs. 2009;69(1):101-13 3. Shastri N. Intravenous acetaminophen use in pediatrics. Pediatr Emerg Care. 2015;31:444-8.

4. Zhu A, Benzon HA, Anderson TA. Evidence for the efficacy of systemic opioid-sparing analgesic in pediatric surgical populations: a systemic review. Anesth Analg. 2017;125:1569-87 5. Veyckermans F, Anderson BJ, Wolf AR, Allegaert K. Intravenous paracetamol dosage in the neonate and small infant. Br J Anaesth.

2014;112(2):380-94 6. Palmer GM, Atkins M, Anderson BJ, Smith KR, et al. IV acetaminophen pharmacokinetics in neonates after multiple doses. Br J Anaesth.

2008;101(4):523-30 7. Nahum E, Friedman M, Kaplan E, Weissbach A, et al. The Hemodynamic Effect of Intravenous Paracetamol in Children: A Retrospective Chart Review. Pediatric Drugs. 2019;21:177-83 8. Nahum E, Weissbach A, Kaplan E, Kadmon G. Hemodynamic effects of intravenous paracetamol in critically ill children with septic shock on inotropic support. Journal of Intensive Care. 2020;8:14. SF

To com plete the quiz , go t o w w w . medicala cademic .c o.za and clic k on t h e CPD ta b

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Acne therapy redesigned An innovative treatment option for acne vulgaris – combining clindamycin (1%) and tretinoin (0.025%) – was launched in South Africa in November, by Viatris. This new gel combination formulation is indicated for patients ≥12-years with moderate acne vulgaris when papules and pustules are present.

T

his article is based on presentations made at the virtual launch of the new combination treatment, sponsored by Viatris/Mylan. The keynote speakers were Emeritus Prof Harald Gollnick, Drs Willie Visser, and Pholile Mpofu.

Current clinical management of acne in South Africa

Dr Willie Visser, Head of Dermatology at University of Stellenbosch, Tygerberg Academic Hospital (Western Cape) Acne vulgaris is a common, sebaceous skin condition caused by the blocking of hair follicles. Due to hormonal influences, the sebaceous gland enlarges and more sebaceous fluid is produced, which accumulates in a blocked pore, causing a waxing, solidified sebum.1 This environment is conducive to the proliferation of bacteria, which may lead to the formation of an open or closed comedone. If the comedone ruptures and disperses the bacteria into the skin tissue – as opposed to on the skin’s surface – the body responds with inflammation to fight the bacteria. This inflamed lesion forms

a papule, which can result in permanent scarring if not treated early and effectively.1 Numerous studies have shown that acne negatively impacts the psychological wellbeing and quality of life of patients, which may result in depression, anxiety, and social isolation.1 Close to 100% of teenagers develop acne at some point. However, it is a misnomer that acne does not affect older people.

A significant number of patients either continue to experience acne or develop new-onset acne after the teenaged years.1 A study by Collier et al assessed the prevalence of acne in different age groups.

They found in the age group, 20 to 29 years, the prevalence of acne was 50.9% in women versus 42.5% in men. In those between 30 to 39 years, the prevalence was 35.2% in women and 20.1% in men complained of acne. In the group 40 to 49 years, the prevalence was 26.3% in women versus 12% in men and in those 50 years and older, the prevalence was 15.3% in women and 7.3% in men. 2,12 The authors concluded that acne continues to be a common skin problem past the teenaged years, with women being affected at higher rates than men in all age groups.2,12

What causes acne?

Patients should be viewed holistically and factors that may cause acne should be discussed at their first visit.

Examples include:1 _ Nutrition: skim milk, assimilated saccharides, nibbling, and nutritional supplements containing whey protein/ leucine. Dr Visser did point out that the role of nutrition as a cause of acne is controversial _ Medication: contraceptives (type of progestin used) and the use of anabolic steroids or testosterone _ Occupational: Cosmetics and mechanical factors _ Pollution: air and industrial pollutants, tobacco, and cannabis use _ Climate: heat, humidity, ultraviolet radiation _ Psychological: stress _ Smoking status.

Factors that guide treatment Dr Visser explained that different treatment modalities are recommended based on:1 _ Lesion/acne type: blackheads, pimples, cysts, scarring The type of lesion should guide the

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approach to acne management. The overall aim of treatment is to prevent permanent scarring _ The grade of acne: mild, moderate, or severe The grade of acne determines whether or not treatment should be intensified.

About 75% of patients have mild to moderate acne and can be managed in general practice. The remaining 25% develop severe disease and must be managed by a dermatologist • Mild (grade 1): there are two types of comedones: open and closed. Open comedones are due to plugging of the pilosebaceous orifice by sebum on the skin surface. Closed comedones are due to keratin and sebum plugging the pilosebaceous orifice below the skin surface. Treatment includes topical therapies • Moderate (grade 2): inflammatory papules present as a small papule with erythema. Treatment with topical (combination products) and/or systemic therapies is recommended • Moderate (grade 3): pustules/ pimples are present. Treatment with topical (combination products) and/or systemic therapies is recommended • Severe (grade 4): many pustules coalesce to form nodules and cysts.

Treatment with systemic retinoids is recommended.

Topical therapies Topical retinoids should be used in almost all acne patients, stressed Dr Visser.

Topical therapies include retinoids, benzoyl peroxide, topical antibiotics, azelaic acid, combinations of clindamycin plus retinoids or benzoyl peroxide and retinoids. He cautioned that antibiotic use could lead to resistant Cutibacterium acnes, especially when using erythromycin, which may lead to resistance to all tetracyclines.

Staphylococcus epidermidis is also a concern. The plasmids may transfer this into resistance to Staphylococcus epidermidis – a situation you want to avoid if you are treating patients with acne.1 He added that ‘spot treatment’ is ineffective. Topical preparations should be applied daily over the entire area affected and treatment should be continued even after clearance.1

Systemic therapies Systemic therapies include antibiotics, hormonal therapy (eg the pill and antiandrogens for use only in females) is a safe option, retinoids and dapsone.

Systemic antibiotics are anti-inflammatory and -bacterial.1

Systemic antibiotics and hormonal therapies have a delayed onset of action and take between three and four months for improvements to become visible.

Dr Visser recommended starting female patients on hormonal therapy early in the onset of the condition. He noted that not all contraceptives are effective, adding that depo provera, nuristerate, and triphasil are not skin-friendly and should not be used in patients with acne.1 Systemic antibiotics should be used in combination with topical products to reduce the risk of resistance development.

There is no rationale for using it as monotherapy, Dr Visser pointed out.1 Systemic retinoids should be used when cysts and nodules are present if other therapies have failed after three to four months of use and when prevention of scarring is the objective. In addition, systemic retinoids can be used if the patient presents with gram-negative folliculitis after prolonged antibiotic use. Systemic retinoids are associated with side-effects such as dry lips (100%), dry nose (66%), dry skin (50%), dry eyes (40%) and acne worsening (35%).1 The relationship between isotretinoin treatment for acne and depression is controversial. A meta-analysis did not show a positive association between isotretinoin use and depression. In fact, it showed that depression declined after use, said Dr Visser.1 However, he cautioned, individual susceptibility to depression during isotretinoin use cannot be ruled out and patients should be made aware of this risk.1 _ Other factors: age, sex, pregnancy, and other comorbidities such as atopic dermatitis. Topical retinoids are not recommended in pregnant patients as it may cause foetal abnormalities.1

Maintenance therapy Maintenance therapy is required for six months to a year after resolution of acne.

In the majority of cases, acne only resolves at around the age of 25. Topical retinoids or azelaic acid are recommended for maintenance therapy. Topical retinoids are preferred because azelaic acid has been associated with skin irritation. In patients who present with inflamed papules, combination therapy is recommended.

Combined contraceptives work well for maintenance in female patients.1 Acne should be viewed as a chronic condition. Therefore, it is extremely important to educate your patients about basic skin care as well as sun protection, he concluded.1

Introducing Clin-RA, a unique formulation

Prof Harald Gollnick, Department of Dermatology and Venereology, Medical Faculty Otto-von-GuerickeUniversity (Germany) Guidelines promote the combined use of treatments with different modes of action in order to modulate two or more acne aetiological factors simultaneously, resulting in faster onset of action and/or greater efficacy.3 The current best practice is to use topical retinoids at the onset of therapy even in patients presenting with predominantly inflammatory acne. In these patients, topical or oral antibiotics or -microbials should be added to provide a significantly greater and more rapid effect.4 An effective strategy is to initiate topical retinoid therapy at the same time as oral or topical antibiotics or -microbials and continue until reasonable clearance of inflammatory lesions occurs.4

Benefits of combination therapy According to Prof Gollnick, combination therapy is effective because it targets more than one pathogenic factor simultaneously.

Combinations that treat bacterial colonisation have anti-inflammatory effects and control comedogenesis (eg an antibiotic-retinoid combination). Using these combinations is more rational and effective, he stressed.1 Combination therapy with a topical retinoid and an antibiotic can normalise follicular epithelial desquamation and reduce bacterial proliferation. The new retinoids have an additional antiinflammatory action along with their effect on the preclinical microcomedo and, co-administered with a topical or an oral antibiotic, are a rational initial therapy for all but the most severe forms of acne.5

An innovate formulation for acne Clindamycin (1%) and tretinoin (0.025%) (Clin-RA) is an aqueous gel formulation containing solubilised clindamycin phosphate 1% and a stable combination of both solubilised and crystalline tretinoin 0.025%. Clin-RA has been evaluated in three pivotal phase III studies, among other studies including a 52-week trial.8,9 Dréno et al evaluated the efficacy and safety of Clin-RA in three 12-week randomised studies. The objective of these studies was to pool the data in order to evaluate the efficacy and safety of Clin-RA in all participants as well as subgroups (adolescents) and acne severity.9 The studies recruited 4550 patients, who

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were randomised to Clin-RA, clindamycin, tretinoin and vehicle. The researchers evaluated Evaluations included percentage change in lesions, treatment success rate, proportions of patients with ≥50% or ≥80% continuous reduction in lesions, adverse events, and cutaneous tolerability.9 Inflammatory, non-inflammatory and total lesions were reduced in the overall study group, as well as significantly higher success rates with Clin-RA compared with clindamycin, tretinoin and vehicle alone.9 In the adolescent group (n=2915), reduction in all types of lesions was also significantly greater with Clin-RA versus comparators. In patients with mild/moderate acne (n=3662 patients) similar results were reported and in those with severe acne (n=880), the percentage reduction in all lesion types was significantly greater with Clin-RA versus vehicle. At 12 weeks, a greater proportion of patients treated with Clin-RA had a ≥50% or ≥80% continuous reduction in all types of lesions compared with clindamycin, tretinoin and vehicle.9 In the active and vehicle groups, adverse event (AE) frequencies were similar and mean tolerability scores over time were <1 (mild) were similar in all groups. The team concluded that Clin-RA is safe, has superior efficacy to its component monotherapies and should be considered as one of the first-line therapies for mild-to-moderate facial acne.9 Another advantage of Clin-RA is that it is not associated with acne flaring or an increase in clindamycin-resistant Cutibacterium acnes (formerly Propionibacterium acnes) counts.

Clin-RA is considered as effective as an adapalene 0.1%/benzoyl peroxide 2.5% fixed dose formulation but has a more favourable tolerability profile.10 Clin-RA may be more effective than clindamycin 1%/benzoyl peroxide 5% at treating non-inflammatory acne lesions since the latter does not contain a retinoid to target comedones. Clin-RA is also easy for patients to manage and apply and has the advantage of not containing benzoyl peroxide, which can bleach hair and fabrics. Taken together, the profile of Clin-RA suggests Clin-RA to be a first-line treatment for patients with facial acne.10 Speed is of the essence when dealing with acne patients in general and teenagers in particular, said Prof Gollnick. Teens have zero tolerance for delayed gratification.6 The onset of action of Clin-RA is rapid, occurring within two weeks of treatment initiation. As shown by Dréno et al, a greater proportion of Clin-RA treated patients had a ≥50% or ≥80% continuous reduction in all types of lesions at week 12 compared with clindamycin, tretinoin and vehicle.9,10

Simple regimens preferred Regimen complexity encompasses dosing frequency, number of medications and ease of administration. Dosing frequency is one of the most important characteristics in drug choice. Adherence decreases dramatically as dosing frequency increases. Patients do not enjoy layering multiple products, especially on the face and especially if they have to be applied during daytime.6 Yentzer et al randomised participants (n=26) with mild to moderate acne vulgaris to 12 weeks of a once daily application of combination Clin-RA, or separate daily applications of clindamycin phosphate gel 1.2 % and tretinoin cream 0.025% (C gel + T cream) twice daily.7 The team measured disease severity at baseline and then again at weeks four, eight, and 12. They also monitored adherence using electronic monitoring caps on the medication tubes.7 Their results showed that median adherence in the Clin-RA group was 88% versus 61% in the C gel + T cream group.

The group randomised to Clin-RA had a mean reduction of 51% mean in total lesions versus a mean of 32% reduction compared to those in the C gel + T cream group by the end of the study.7 The authors concluded that both Clin-RA and separate applications of C gel + T cream improved mild to moderate acne, however, the use of a once daily combination product improved adherence and thus clinical outcomes.7

Patient preference Kellett et al compared patient preferences for four topical antibiotics used for one week, once or twice daily, to treat acne vulgaris. This was a randomised, phase IV, single-centre, cross-over study was performed using conjoint analysis and a traditional patient questionnaire.11 Participants used each of four topical antibiotics for 1 week: erythromycin/zinc solution, clindamycin phosphate lotion, benzoyl peroxide/erythromycin gel (each applied twice daily) and clindamycin phosphate gel (applied once daily) over a four week period.11 The study looked at five different attributes of acne medications: form, storage, product life once opened, method of application and regimen (each with two or three possible options). The researchers identified 108 possible permutations focusing on the five attributes mentioned above and selected, 16 hypothetical medications at random, which were described on printed cards.11 Participants (=67) were asked to rank the cards in order of preference and which

hypothetical product they were most likely to use. The ratings were done pre- and post-treatment. The team then calculated product utilities using a multiple regression model for each patient.11 In addition, participants were asked to complete an acceptability questionnaire.

They had to rate the product acceptability after one week of treatment with each of the four topical antibiotics. Later, they were asked to rank the medications in order of preference after using all four treatments.

Tolerability was assessed using diary cards.11 A total of 64 participants used all four medications and completed the study. The analysis showed that a gel formulation, room temperature storage, product life of up to 18 months once opened, application with fingers and once-daily regimen were ranked first for the five product attributes.

Out of the 108 possible product permutations, clindamycin phosphate gel had the highest ranking pre and posttreatment (six and one respectively) and benzoyl peroxide/erythromycin gel had the lowest rankings (93 and 70 pre- and post-treatment).11 The results of the questionnaire indicated that the highest proportion of participants (33%) ranked clindamycin phosphate gel as number one. Clindamycin phosphate gel was also ranked first in terms of overall satisfaction, followed by clindamycin phosphate lotion, benzoyl peroxide/erythromycin gel and erythromycin/zinc solution.11 The most AEs were reported with the erythromycin/zinc solution and benzoyl peroxide/erythromycin gel. Clindamycin phosphate gel was the only product not associated with any episodes resulting in a change of medication or dose.11 In terms of topical antibiotic preference, participants clearly preferred a gel formulation that could be applied with the fingers once daily and stored at room temperature for as long as 18 months.11 The authors concluded that clindamycin phosphate gel combined all five of the preferred attributes, which was confirmed by the simulated product rankings as well as the questionnaire.11

Unmet needs in treating acne

Dr Pholile Mpofu, Dermatologist and clinical researcher

Patient adherence to therapy is a major obstacle in the effective management of acne, leading to high failure rates. Studies show that only 75.8% of patients adhere

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to topical treatment. Factors that influence patient adherence include:1 _ Primary causes • Treatment is not started at all • Patient lack of knowledge about his/ her condition • Confusion about how to use medication • Weak patient-doctor relationship • Fear of adverse events • Cost _ Secondary causes (started, but abandoned) • Delayed results • Complexity of regimens • Side effects (skin irritation and inflammation) • Busy lifestyles • Forgetfulness • Inconvenience • Psychiatry comorbidities.

According to Dr Mpofu, studies show that patients prefer treatment that is effective and has a rapid onset of action. Products that address inflammatory and noninflammatory lesions are also preferred.

Furthermore, products that are userfriendly, easy to apply and do not lead to antibiotic resistance, are preferred.1 Dr Mpofu emphasised the importance of managing patient expectations. Explaining to the patient what to expect (eg delayed onset of action) from treatment will improve adherence. It is also extremely important to make patients aware of the consequences of non-adherence to treatment such as permanent scarring.1 It is also extremely important to rule out conditions that may mimic acne, because these conditions require a different approach to treatment. Conditions that may mimic acne include:1 _ Pseudofolliculitis: also known as ‘shaving bumps’, or ‘razor bumps’, is inflammation of hair follicles and surrounding skin, caused by hairs trapped beneath the skin surface. The condition is more common in men and usually occurs on the face.

Symptoms include clusters of small, red, or dark bumps around hair follicles. The surrounding skin is often red and inflamed _ Gram-negative folliculitis: a pustular rash resembling acne caused by a bacterial infection. Lesions are usually found around the area of the upper lip under the nose, to the chin and cheeks _ Demodex folliculorum: caused by a saprophytic parasitic mite of the pilosebaceous follicle and seborrheic glands and is found mainly on the face of adult men. The condition is characterised by itchy pustules, follicular scaling, and dryness, conglobata demodicosis with nodulocystic lesions, and blepharitis _ Eosinophilic folliculitis: a non-infectious

eosinophilic infiltration of hair follicles. The three variants include classic eosinophilic pustular folliculitis, immunosuppressionassociated eosinophilic folliculitis (mostly HIV-related), and infancy-associated eosinophilic folliculitis. Patients with eosinophilic folliculitis develop recurrent crops of sterile pustules and papules.

Pruritus develops in half of the patients, in some cases with considerable intensity.

The clinical course of eosinophilic folliculitis is characterised by multiple cycles of exacerbations and remissions _ Pityrosporum: occurs when a specific genus of yeast called Malassezia, which naturally occurs on your skin, infects the hair follicles. Pityrosporum folliculitis lacks comedones, which are the whiteheads and blackheads that are common characteristics of acne. It is very itchy condition and tends to occur in areas where the skin is oilier (T-zone) _ Peri-oral dermatitis: small, red, pus-filled bumps and mild peeling of the skin around the mouth. The condition can also affect the skin around the nose, cheeks, and eyes _ Rosacea: a condition that causes redness and often small, red, pus-filled bumps on the face. Key symptoms are facial redness with swollen red bumps and small visible blood vessels _ Pomade acne: acne eruptions on the forehead and temples consisting mainly of rather uniform closed comedones with occasional papulo-pustules. May be caused by excessive use of hair products.

In the majority of cases, pomade acne will resolve when use of products are stopped _ Mask acne: a common side effect of using a mask. Taking off the mask regularly (when possible) and good skin hygiene may help to improve skin health _ Steroid acne: an acne-like skin condition that occurs in people with high levels of circulating corticosteroids. They may have Cushing disease or they may be undergoing treatment with systemic steroid medications. May also be a side effect of the use of anabolic steroids.

Take-home messages

1

2

Acne has a negative effect on emotions and social functioning Good acne treatment means: Choice of the right drug (effective, fast action, well tolerated, long-term tolerability, easy to use, does not cause antibiotic resistance) leads to improvement of adherence to treatment Effective patient education should start at the first visit

3

4

Acne can occur at any age

5 6

It is important to eliminate other causes that mimic acne Managing patient expectations is crucial to the success of treatment.

References 1. Viatris Treclin launch. 16 November 2021. https:// cpdlive.co.za/viatris-treclin-launch/ 2. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol, 2008.

3. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol, 2007.

4. Gollnick HPM, Cunliffe W, Berson D, et al.

Global Alliance to Improve Outcomes in Acne.

Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol, 2003.

5. Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol, 2003.

6. Baldwin HE. Tricks for improving compliance with acne therapy. Dermatologic Therapy, 2006.

7. Yentzer BA, Ade RA, Fountain JM, et al.

Simplifying regimens promotes greater adherence and outcomes with topical acne medications: a randomized controlled trial. Cutis, 2010.

8. Del Rosso JQ, Jitpraphai W, Bhambri S, Momin S. Clindamycin phosphate 1.2%- tretinoin 0.025% gel: vehicle characteristics, stability, and tolerability. Cutis, 2008.

9. Dréno B, Bettoli V, Ochsendorf F, et al. Efficacy and safety of clindamycin phosphate 1.2%/ tretinoin 0.025% formulation for the treatment of acne vulgaris: pooled analysis of data from three randomised, double-blind, parallel-group, phase III studies. Eur J Dermatol, 2014.

10. Ochsendorf F. Clindamycin phosphate 1.2% / tretinoin 0.025%: a novel fixed-dose combination treatment for acne vulgaris. J Eur Acad Dermatol Venereol, 2015.

11. Kellett N, West F, Finlay AY. Conjoint analysis: a novel, rigorous tool for determining patient preferences for topical antibiotic treatment for acne.

A randomised controlled trial. Br J Dermatol, 2006.

12. Heng AHS, and Chew FT. Systematic review of the epidemiology of acne vulgaris. Sci Rep 10, 5754 (2020). https://doi.org/10.1038/s41598-02062715-3. SF

Disclaimer

The content contained in this publication contains medical or health sciences information and is intended for professional use within the medical field. Discussions views and recommendations as to medical procedures, products, choice of drugs and drug dosages are the views of the authors.

The views expressed by the editor or authors in this newsletter do not necessarily reflect those of the sponsors or publishers. The sponsors, publishers and editor will not be liable for any damages or injuries of any kind arising from the use or misuse of information provided in this publication and do not support the use of products for off label indications.

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Photo credit: Shutterstock.com

This article was independently sourced by Specialist Forum.

Treating superficial skin infections

Topical antibacterials are commonly used for superficial skin infections, cuts, abrasions, burns, and surgical wounds. Several topical antibiotics are available for use in different indications. Impetigo and folliculitis are two of the most common bacterial skin infections seen in primary care and fusidic acid is indicated as first-line option for both.1,2,6,7

I

mpetigo is a common superficial bacterial infection most often seen in children. There are two forms of impetigo non-bullous and bullous. The non-bullous form is the most common (70%) and generally affect children between two and five years, while those under the age of two are more affected by the bullous form.3 The non-bullous form presents with an erosion (sore), cluster of erosions, or small vesicles or pustules that have an adherent or oozing honey-yellow crust. The bullous form of impetigo presents as a large thinwalled bulla (2cm to 5cm) containing serous yellow fluid. It often ruptures leaving a complete or partially denuded area with a ring or arc of remaining bulla. 2,3 Lesions can develop anywhere on the body but are most common on the face.

It is a self-limiting, non-scarring condition, which usually resolves in two to three weeks without treatment. 3 Complications are uncommon. However, untreated individuals remain infectious.

To prevent outbreaks, children should not attend school or other childcare institutions until lesions are crusted and healed, or for 48 hours after commencing treatment.

Good hygiene measures (eg washing hands regularly and using separate towels) help prevent spread of impetigo to other areas of the body and to other people.3 Folliculitis is caused by bacterial infection of the superficial or deep hair follicle.

However, this condition may also be caused by fungal species, viruses and can even be non-infectious in nature. Several of the causative agents of folliculitis are listed below and include:4 _ Superficial bacterial folliculitis: the most common form of folliculitis, this particular condition is usually caused

by the bacteria S. aureus. It should be noted that both the methicillin-sensitive and methicillin-resistant forms of this bacteria can cause folliculitis. _ Gram-negative bacterial folliculitis: commonly referred to as ‘hot tub’ folliculitis, this condition results from the bacteria pseudomonas aeruginosa.

It typically arises after exposure to contaminated water from either an improperly treated swimming pool or hot tub. Other bacteria that may cause this condition include Klebsiella and Enterobacter. Folliculitis from these bacteria commonly arises after longterm use of oral antibiotics. _ Pityrosporum folliculitis: this particular form of folliculitis is fungal, caused by the Malassezia species of fungi such as Malassezia furfur. Typically found in adolescence secondary to increased activity of their sebaceous glands and is commonly found in a cape-like distribution over the patient’s shoulders, back, and neck. Clinical suspicion of this condition should arise in patients diagnosed with acne that has failed to respond or even worsened, after antibiotic treatment. _ Viral folliculitis: most commonly caused by herpes virus it could also be caused

by Molluscum contagiosum, but this is far rarer. Folliculitis due to herpes virus presents in much the same way as bacterial folliculitis with the exception that papulovesicles and/or plaques are usually present and not pustules.

Another key to the diagnosis of this condition is that lesions typically appear in either groups or clusters. _ Demodex folliculitis: a type of folliculitis caused by the mite Demodex

folliculorum. this particular type of folliculitis is controversial as the Demodex mite normally presents in the pilonidal sebaceous area of the skin.

Estimates are that 80% to 90% of all humans may carry this mite. _ Eosinophilic folliculitis: this particular brand of folliculitis is found predominantly in those with advanced HIV or those with low CD4 counts. Although a nonHIV variation of this condition has been seen as a rare side effect in patients undergoing chemotherapy. While the exact aetiology of this condition is unknown, studies suggest it could result from inflammatory disease secondary to immune dysregulation and that there may be an associated underlying infection. Most commonly, this condition presents as erythematous and urticarial follicular papules, usually on the scalp, face, and neck with rare pustules.

Oral or topical antibiotics?

According to current recommendations, topical antibiotics are only recommended in cases of mild to moderate or superficial infections. Patients with severe disease who are systemically unwell will require assessment in hospital for monitoring and intravenous antibiotics.5 Fusidic acid and mupirocin are two of the most commonly used antibiotics for the treatment and eradication of skin infection.

Topicals antibacterials are eminently suitable for targeted drug delivery by taking the drug directly to the site of action, thus ensuring excellent bioavailability of antimicrobials at the infected tissue. The other advantages of topical usage of antimicrobials are the small amounts of drugs used, low cost, and noninterference with intestinal microbial flora.1

MASTERING THE ART AGE OF M RIT OR E H

H AN ET

With

PROU D

OF BACTERIAL SKIN INFECTION TREATMENT

YEARS 1

THE DERMATOLOGIST'S AND GP'S

№1

PRESCRIBED BRAND FOR BACTERIAL SKIN INFECTIONS2

Just as a Bonsai tree requires great care and patience to grow into the masterpiece it is today, great care has been taken with FUCIDIN® to ensure that it remains THE NUMBER 1 PRESCRIBED BRAND of South African dermatologists and GPs in the treatment of topical bacterial skin infections.*2 *Impetigo and/or staphylococcal primary skin infections References: 1. Schofer H, Simonsen L. Fusidic acid in dermatology: an updated review. Eur J Dermatol 2010;20(1):6-15. 2. Impact Rx, June 2021.

FUCIDIN® CREAM. Each gram contains 20 mg (2 % m/m) fusidic acid. Reg. No. Q/20.1.6/128. FUCIDIN® OINTMENT. A 20.1.6. Each gram contains 20 mg sodium fusidate. Ref. No. G2410 (Act 101/1965). Under license from LEO Pharmaceutical Products, Ballerup, Denmark. For full prescribing information refer to the package insert approved by the medicines regulatory authority.

Adcock Ingram Limited. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021, South Africa. Telephone + 27 11 635 0000. www.adcock.com. 17554N. 2021071310137597.

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Why fusidic acid is the first-choice option in the treatment of skin infections Fusidic acid is an antibiotic derived from the fungus Fusidium coccineum. Fusidic acid acts by inhibition of bacterial protein synthesis by preventing translocation of the elongation factor G from the ribosome.

Fusidic acid has a steroid-like structure without the unwanted side effects of steroid.1 Pharmacokinetic and pharmacodynamic studies have shown that, contrary to other topical antibiotics such as gentamicin or mupirocin, fusidic acid reaches high antimicrobial concentration at deep skin layers after topical application either on intact or damaged epidermis.9 Several randomised controlled trials demonstrated that fusidic acid, in its various topical formulations, is very effective in treating skin infections, given its high bactericidal activity against S. aureus (including strains resistant to penicillin, methicillin, ampicillin, cloxacillin), S. epidermidis, Streptococcus pyogenes, Propionibacterium acnes, Corinebatteria, Clostridia.9 Additionally, fusidic acid presents a low risk of resistance even in methicillin-resistant S. aureus strains, a common pathogen implied in the aetiology of skin infections.9 Studies using either fusidic acid cream or ointment have shown that there is fast and effective healing of skin infections. Studies

Treating impetigo Therapy depends on the extent and site of the lesions and on the presence of systemic symptoms. The practical clinical recommendations suggest topical antibiotic therapy for localised lesions and systemic therapy with oral antibiotics in cases of extensive injury, failure, or inability to perform topical therapy.5 Topical treatments are likely to cause fewer side-effects, and applying a cream is usually straightforward for localised impetigo. Palatability and frequency of dosing of oral antibiotic liquids can be challenging in young children.3 In widespread non-bullous impetigo, clinicians should choose either a topical or oral antibiotic treatment after considering the distribution of the lesions and the wishes of the patient or parent/carer.

Whether topical or oral treatment is used, a five-day course should be prescribed.

This can be increased to seven days based on clinical judgement, depending on the severity and number of lesions.3 Fusidic acid is one of the most frequently prescribed topical agents for the treatment of impetigo. It acts against grampositive bacteria such as Staphylococcus

in mainly primary skin infections, such as impetigo, abscesses/boils, folliculitis, and paronychia, and including a few cases of infected wounds and other secondary infections, have demonstrated response rates of between 86% and 100%, with treatment duration or mean healing time varying between four and 7.1 days.10 A study examining the clinical efficacy of topical fusidic acid ointment applied once daily compared with that of three oral antibiotics given for five days: 150mg clindamycin, 250mg flucloxacillin or 250mg of erythromycin four times daily plus placebo ointment. A total of 90 patients with skin infections including infected wounds, paronychia, and abscesses/ boils, were included. The mean healing time in patients receiving oral antibiotics was grouped and compared with that in patients using fusidic acid ointment. A significantly more rapid healing time in soft tissue infections was shown for fusidic acid ointment compared with the oral antibiotics (7.1 days vs. 9.7 days).10 A double-blind three-arm comparative study compared the effects of fusidic acid ointment plus placebo amoxicillin, placebo fusidic acid ointment plus amoxicillin, or fusidic acid ointment plus amoxicillin in 90 patients in the treatment of furuncles, carbuncles, impetigo, and infected wounds.10

Fusidic acid ointment was as effective as amoxicillin, and there was no further improvement in clinical outcome when the treatments were used in combination.

Fusidic acid ointment is as effective as mupirocin ointment but has superior patient acceptability.10 A study involving 354 patients with primary or secondary skin infections, randomised participants to receive either mupirocin or fusidic acid three times daily for up to seven days. There was no difference between the two preparations in outcome in either primary or secondary infections.10 However, adverse events were reported in 1% of the fusidic acid ointment group, compared with 7.4% of those using mupirocin ointment. The greasy, messy, or sticky nature of mupirocin ointment accounted for the majority of complaints.10 Such feature makes fusidic acid particularly useful in the management of these medical conditions. Finally, possibly due to its large steric effect, fusidic acid has proved a very low risk of contact sensitisation. Overall, data on fusidic acid efficacy, safety, sensitisation potential, resistance profile and spectrum selectivity make it a first-choice option in the treatment of primary and secondary skin infection.9

species and Corynebacterium species.1 The 2020 National Institute of Health Care and Excellence impetigo guidance recommends fusidic acid as first-line topical antibacterial treatment.6

Recommended treatment include:8 _ Mild, superficial folliculitis may resolve without treatment _ Consider treating nasal carriage of S. aureus with topical Fucidin® in those with recurrent folliculitis _ Topical antiseptics such as triclosan, clorhexidine or povidone-iodine may be used to treat and prevent superficial folliculitis _ For deeper folliculitis, topical or oral antibiotics are usually required _ In severe or recurrent cases, antibiotic therapy may be required for four to six weeks _ Other antibiotics may be used depending on culture results and the degree of clinical suspicion of alternative causative organisms – eg pseudomonal folliculitis responds to oral ciprofloxacin. _ Gram-negative folliculitis can be treated as for severe acne, with isotretinoin but use of isotretinoin is associated with major side-effects, including birth defects _ Fungal infections are usually treated with topical azoles _ Aciclovir or similar agents can be used to treat herpetic folliculitis.

References are available on request. SF

Folliculitis Without treatment, bacterial folliculitis may progress to hard and painful lumps filled with pus, known as boils. Various interventions have been suggested for treating folliculitis and boils, including local application of moist heat, phototherapy, antiseptic agents, antibiotics alone, or combination therapy.7 Local moist heat around 38°C to 40°C applied for 15 to 20 minutes may increase local blood flow, may establish drainage, and has proved helpful in treatment of newly emerged folliculitis or boils.7 Topical antibiotics such as fusidic acid 2% cream twice daily may be used in treating folliculitis or boils when the number of lesions is limited, or they may be used in combination with other interventions.

Systemic antibiotics may be used for treating folliculitis and boils, especially when systemic symptoms such as fever, lymphadenitis, or cellulitis appear.7

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This article was independently sourced by Specialist Forum.

People with dermatitis at high risk of osteoporosis, major fractures

A recent study found that people with atopic dermatitis (AD) or eczema, have an increased risk of fracture - particularly major osteoporotic fractures.1,2

T

he study by Lowe et al , the largest to date to examine the relationship between AD and fractures, was published in the February 2020 issue of The Journal of Allergy and Clinical Immunology. The team found a strong association between the risk of fracture and the severity of AD. The strongest associations were found in people with severe AD (compared to those without) for spinal, pelvic, and hip fractures.1

The link AD is a common, chronic, pruritic

inflammatory skin disease, occurring in about 10% of adults. Its onset is generally at a young age and follows a relapsing course.

AD is often associated with elevated serum immunoglobulin levels and a personal or family history of type I allergies, allergic rhinitis, and asthma.1,2 The International Osteoporosis Foundation defines osteoporosis, which means porous bone, as a disease in which the density and quality of bone are reduced. As bones become more porous and fragile, the risk of fracture increases greatly. The loss of bone occurs silently and

progressively. Often there are no symptoms until the first fracture occurs. Reducing fractures is an important public health goal because fractures are associated with increased morbidity and mortality.1,4 According to Garg et al (2014) patients with AD have multiple potential risk factors for decreased bone mineral density (BMD), including using large quantities of topical and systemic corticosteroids (CS). These patients are also at high risk of chronic inflammation. Furthermore, AD is associated with distraction from itch, mental health comorbidities, and sleep

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disturbance, all of which predispose to fractures and other injuries. 3 Haeck et al (2009) found that about 33% of adults with moderate to severe AD have low BMD as measured by dual-energy x-ray absorptiometry. Diseases characterised by chronic inflammatory states are associated with bone loss and skeletal remodeling.5 In another study by Garg and Silverberg (2015), the authors found higher prevalence of fracture and bone or joint injury, and other types of injury, causing limitation among adults with AD. These associations remained significant after controlling for the effects of comorbid atopic disease and psychiatric and behavioural disorders, suggesting a specific association between adult AD and an increased risk of injury.6

An estimated 1.4 million females aged and 0.6 million males aged over 50 have osteoporosis8

AD was associated with higher odds of fracture and bone or joint injury for all individuals 30 years or older, with the largest effect at ages 50 to 69 years.

Significant interactions were observed between AD and fatigue or sleep symptoms, such that adults with AD had an increased risk of injury above and beyond the presence of concurrent sleep disturbance or fatigue.6 In addition, adults with both AD and fatigue or sleep symptoms had higher rates of fracture and bone or joint injury compared with those with AD or fatigue or sleep symptoms alone.6 Similarly, adults with both AD and psychiatric and behavioural disorders had higher rates of fracture and bone or joint injury compared with those with AD or psychiatric and behavioural disorders alone.

These interactions suggest that adults with more severe AD accompanied by sleep and psychiatric and behavioural disorders comorbidities are at particularly higher odds of fracture and bone or joint injury.6 Wu et al (2017) found that the overall incidence of osteoporosis was 4.72-fold greater in AD patients compared to

the non-AD patients (1.82 vs. 0.24 per 1,000 person-years, respectively) after adjusting for potential confounding factors. Osteoporosis risk factors included female gender, age, advanced Charlson Comorbidity Index, depression and use of CS. The dataset analysis showed that AD was significantly associated with subsequent risk of osteoporosis.7

Findings from the new study According to Lowe et al the aim of their study was to bolster ‘limited’ evidence of a link between AD and osteoporosis. Their study included data from 526 808 people with AD and 2 569 030 people without AD. They also looked at whether fracture risk varies with AD severity.1 They found strong evidence of an association between AD and increased hip, pelvic, spinal, and wrist fractures after adjusting for calendar period, index of multiple deprivation, and asthma (implicitly adjusted for age, sex, general practice, and date of cohort entry).

There was weaker evidence for an increase in proximal humeral fractures.

For any fracture, the hazard ratio (HR) comparing the risk of fracture in those with and without AD was 1.10.

The greatest increased risk was seen for spinal fracture (HR 1.18). The unadjusted absolute rate for any fracture in those with AD was 1428 fractures per 100 000 personyears, an excess of 164 fractures per 100 000 person years compared with matched individuals without AD. After further adjusting for potential mediators (BMI, smoking, harmful alcohol use, and high-dose oral glucocorticoid use), the association between AD and fracture was slightly attenuated (eg HR for any fracture in those with AD compared with those without after additionally adjusting for potential mediators of 1.07) compared with HR adjusted for calendar period, index of multiple deprivation, and asthma of 1.10. The team found similar attenuation of effect estimates across all of the major osteoporotic fractures investigated.

The team recorded minimal change in effect estimates for the association between AD and fracture in most sensitivity analyses.

However, when those with a previous history of any type of fracture were excluded from analyses of specific fracture outcomes: For pelvic, wrist, and proximal humeral fractures, the HRs comparing fracture risk in those with and without AD were reduced For spine and hip fractures, HRs were attenuated, but the increased risk of fracture remained.

1

2

AD severity and fracture risk Risk of fracture increased with increasing AD severity. For example, there was a 6% increase in the risk of spinal fracture in people with mild eczema, a 22% increase in those with moderate eczema and a 109% increase in those with severe eczema. The greatest magnitude of increased risk was for spinal fracture in those with severe eczema (HR 2.09), followed by pelvic (HR 1.66) and hip (HR, 1.50) fractures.

The team found varying evidence depending on specific fracture outcomes for age modifying the effect of AD on fracture risk, with some statistical evidence that age modified the effect of AD on spinal (P 5 .0007) and hip (P 5 .0043) fractures.

Similarly, evidence for sex modifying the effect of AD on fracture risk varied depending on specific fracture outcome, with some evidence of a slightly greater risk of hip, wrist, and any fracture associated with AD in men than in women.

Conclusion AD is associated with an increase in fracture risk, particularly among people with severe disease. The increased risk was most pronounced for major osteoporotic fractures. Spinal fracture risk more than doubled in those with severe AD compared with those without AD, whereas hip fracture rates increased by 50% and pelvic fracture rates were increased by 66%.

References 1. Lowe KE, Mansfield KE, Delmestri A et al. Atopic eczema and fracture risk in adults: A populationbased cohort study. The Journal of Allergy and Clinical Immunology, 2020.

2. Eichenfield LF. Tom WL, Berger TG et al.

Guidelines of care for the management of atopic dermatitis. J Am Acad Dermatol, 2014.

3. Garg N and Silverberg JI. Association between eczema and increased fractures, bone or joint injury in adults: a US population-based study.

JAMA Dermatol, 2014.

4. International Osteoporosis Foundation. What is osteoporosis?

5. Haeck IM, Hamdy NAT, Timmer-de Nik L et al.

Low bone mineral density in adult patients with moderate to severe atopic dermatitis. Br J Derm, 2009.

6. Garg N and Silverberg I. Association Between Eczema and Increased Fracture and Bone or Joint Injury in Adults: A US Population-Based Study. JAMA Dermatol, 2015.

7. Wu C-Y, Lu Y-Y, Lu C-C et al. Osteoporosis in adult patients with atopic dermatitis: A nationwide population-based Study. PLoS One, 2017.

8. International Osteoporosis Foundation.

Osteoporosis in South Africa. SF

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This article was independently sourced by Specialist Forum.

www.medicalacademic.co.za

Sun poisoning – it’s real Researchers from the University of the Witwatersrand recently found that our summers last six months. Our love of spending time outdoors may put us at high risk of photodermatoses, also known as sun poisoning.

A

lthough it is not generally lifethreatening, photodermatoses cause considerable suffering.

Some people can go into anaphylactic shock following full body exposure.

Photodermatoses are ‘abnormal’ cutaneous reactions to sunlight induced by excessive UV radiation – even for short periods of time (<30 minutes) – that can take several weeks to resolve. Sunburn on the other hand, is considered a ‘normal’ reaction to the sun, causing redness that go away after a few days.

While not all sunburns require medical attention, all cases of photodermatoses require immediate medical attention. Apart from anaphylactic shock, photodermatoses can cause dehydration, skin lesions, scarring, blisters, scaling, pruritus and hyperpigmentation.

Apart from the physiological impact of photodermatoses, a recent British study showed that 31%-39% of patients experienced a very large impact on their quality of life. Patients had around double the rates of anxiety and depression found in the general population.

Risk factors Polymorphic light eruption (PMLE), which is often incorrectly labelled as sun allergy, is the most common form of the condition (prevalence 10% to 20%). Other, rarer types such as hydroa vacciniforme (characterised by recurrent fluid-filled blisters [hydroa] that heal with pox-like [vacciniform] scars) affects an estimated 0.34 people per 100 000.

People at greatest risk of photodermatoses are those who: » Have fair skin » Have a family history of skin cancer » Are taking antibiotics or oral contraceptives » Use certain herbal supplements, such as St. John’s wort » Apply citrus oils to the skin prior to sun exposure » Live in a region near the equator » Reside in high altitudes (such as mountainous regions) » Spend long periods in the sun – especially

at the beach (sunlight reflects more intensely off sand and water) » Engage in regular snow activities during the winter (sunlight reflects off snow) » Use alpha hydroxy acids (AHAs), such as chemical peels.

Types of photodermatoses Two types of photodermatoses can be distinguished, namely primary and secondary. Primary photodermatoses are induced by photosensitising substances such as industrial chemicals, some

medications (eg antibiotics), some plants and other agents that increase the sensitivity to UV damage.

Secondary photodermatoses are associated with systemic diseases such as lupus erythematosus, metabolic disorders such as porphyrias, or disorders of DNA repair such as xeroderma pigmentosum.

Presentation, treatment and prevention Photodermatoses are divided into: Phototoxic and photoallergic reactions (photosensitisers are known) Idiopathic photodermatoses (photosensitiser are unknown).

1

2

Examples of photodermatoses with known photosensitiser include:

Photoallergic dermatitis Reactions occur after exposure to a specific allergen. Important topical photoallergens include halogenated salicylanilide, fenticlor, hexachlorophene, bithionol, and in rare cases also sunscreens. The skin is slightly inflamed, red, lichenified and scaly. Other signs include erythemas, papular vesicles, severe pruritus, and sometimes blistering. The affected skin areas differ from those parts of the body protected from light by clothing.

Treatment Sun protection using both dense clothing and sunscreen (UV-A filters) is essential.

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Phototoxic dermatitis Phototoxic skin reactions are more common than photoallergic reactions. They usually present as dermatitis and symptoms are similar to sunburn. Phytophotodermatites (grass dermatitis) and phototoxic reactions induced by medications such as tetracyclines are clinically significant. Symptoms are similar to sunburn and include acute dermatitis with reddening, oedema, vesicles or blisters, and often severe pigmentation.

Treatment and prevention The use of all medications and cosmetics with phototoxic actions must be discontinued. Systematic use of fragrancefree sunscreen is essential. Pronounced depigmentation can be achieved using a combination of 0.1% retinoic acid, 5.0% hydroquinone and 1% hydrocortisone.

Occasionally, however, persistent hyperpigmentation develops. In these cases, laser therapy (Rubin laser) can help.

Examples of idiopathic photodermatoses include:

Polymorphous light eruption The cardinal symptom is severely pruritic skin lesions. Skin lesions develop a few hours to several days after sun exposure.

Initially, patchy erythema develops, accompanied by pruritus. Distinct lesions then develop. The upper chest, upper arms, backs of the hands, thighs, and the sides of the face are the primary localisations.

The skin lesions resolve spontaneously within several days of ceasing sun exposure and do not leave behind any traces. Many patients develop tolerance over the course of the sunny period of the year, meaning that ultimately even prolonged sunbathing can be tolerated later in the season.

Treatment and prevention Differentiation between symptomatic treatment of manifested PMLE and prevention is extremely important.

Avoiding further sun exposure should be emphasised as this can lead to the rapid and spontaneous remission of symptoms.

Remission can be accelerated by topical glucocorticoids. Antihistamines may alleviate pruritus, but their value should not be overestimated. The same applies to topical antihistamines. Prevention is extremely important. Light tolerance or hardening can be accelerated using phototherapy before the sunny period of the year. This should only be administered under specialist medical supervision and not in a solarium in order to ensure minimal UV exposure. Topical application of broad-spectrum sunscreen is useful. This predominantly benefits patients with UV-B-induced PMLE. With an extremely low UV-A threshold, PMLE episodes cannot

be prevented even with very potent UV-A filters. General sun protection measures such as covering with clothes and appropriate, sensible behaviour are also useful. An interesting new approach to preventative external therapy involves topical application of suitable antioxidants, because pathophysiologically, inflammatory reactions are most likely mediated by free radicals generated in the skin. Photochemotherapy (PUVA) is exceptionally effective but should, however, be reserved for extremely lightsensitive patients.

Solar urticaria Although rare, solar urticaria is a severe condition that can result in anaphylactic shock. Urticarial skin lesions appear a few minutes after exposure – even if the skin is covered with thin clothing. Patients may report pruritus, erythema, and wheal formation of varying degrees after a short period (<30 min) of sun exposure.

Anaphylactic shock may occur after wholebody exposure.

Treatment PUVA has become established as the method of choice for severe forms of solar urticaria because this procedure can achieve longer remissions (two to three weeks) compared to radiation without psoralene (a few days).

Prior to starting it is recommended to develop tolerance using repeated provocative radiation over the entire integument. PUVA treatment can then be initiated overlapping with this light hardening. After verification of the presence of a plasma factor, which is hypothetically formed by UV absorption and mediates type I reactions, treatment using plasmapheresis can achieve an improvement.

The risk of lymphoproliferative malignancy in children with hydroa vacciniforme and chronic infection by EBv should be observed carefully and follow-up is recommended.

Chronic actinic dermatitis Chronic actinic dermatitis (CAD) is an umbrella term that includes conditions such as persistent light reaction, actinic reticuloid, and photosensitive eczema. CAD is characterised by chronic, usually lichenified dermatitis on sun-exposed skin areas also spreading to other areas which, although covered by clothing, are not adequately protected from the sun. The skin appears inflamed, red and hard. The distressing pruritus leads to excoriation. The most commonly affected sites are the forehead, cheeks, ears, nape, throat, and the backs of the hands and in severe cases the entire integument.

Treatment and prevention PUVA treatment has become the method of choice in addition to systemic glucocorticosteroids, azathioprine and cyclosporine A. Initiating the treatment can be very difficult due to the extreme light sensitivity. Initial doses below the eczema threshold must be selected. A combination of immunosuppressants is useful in this initial phase. A combination of cyclosporine A and PUVA should be avoided due to the risk of photocarcinogenesis. Avoiding radiation that triggers the dermatitis has the highest priority. Due to the large action spectrum, the use of particularly intensive sun protection is important. In extreme cases artificial lighting at work can also contribute to continued persistence of the eczema. Shifting leisure activities to the evening and night, wearing light-blocking clothing, and full-coverage, tinted make-up preparations can also help.

Hydroa vacciniforme Has an acute onset in early childhood and is characterised by necrohaemorrhagic lesions that appear on uncovered areas of skin, which became crusted then gradually heal leaving varioliform scars, hence the denomination. The course is chronic, characterised by periods of activity and remission. Recently, an association has been reported in some cases between latent Epstein-Barr virus (EBv) infections.

Treatment Treatment is based on solar protection, and in severe cases, systemic corticoids can be used. The use of PUVA proved to be beneficial when used before sun exposure. Recent studies described the treatment of hydroa vacciniforme associated with EBv infection with acyclovir/valacyclovir therapy, with a good clinical response. After treatment, the patients reported having less fatigue, rashes, and scars. They were able to spend more time outdoors without causing new eruptions.

Actinic prurigo Onset is in childhood and persists into adulthood. The condition presents as pruriginous skin lesions that develop on chronically sun-exposed areas of the skin such as the face, often centrofacial, the nape, the ears, the backs of the hands and the lower arms. Lichenified erythematous plaques, cushion-like infiltrations, and nodular prurigo develop.

Treatment Treatment is very difficult. The treatment of choice is thalidomide, the use of which must be examined in depth considering the serious adverse reactions (teratogenicity, irreversible neuropathies). Other than that, no local or systemic medication has yet been able to achieve a substantial improvement. Even light hardening using phototherapy has often had little effect on the clinical symptoms.

References available on request. SF

SF | GASTROENTEROLOGY

January 2022 | Vol. 22 No. 1 Photo credit: Shutterstock.com

www.medicalacademic.co.za

This article was independently sourced by Specialist Forum.

Are probiotics the panacea to antibiotic-associated diarrhoea?

An estimated 5%-35% of patients who are prescribed antibiotics, develop antibioticassociated diarrhoea (AAD). Some antibiotics disturb normal gastrointestinal (GI) microflora, which may cause diarrhoea which may cause diarrhoea, ranging from a mild, self-limiting illness to serious and progressive pseudomembranous colitis.

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AD is defined as unexplained diarrhoea (typically ≥3 loose/ watery stools/day for at least two days) that occurs in association with antibiotic therapy. AAD may occur just a few hours after antibiotic administration or up to several months after its discontinuation.

Alterations in the bacterial component of the microbiota, most often due to the use of antibiotics, can lead to ecological changes and growth of Clostridium difficile – recently renamed Clostridioides difficile.

C.difficile is responsible for the most severe cases in 10%-25% of all episodes of AAD, which may lead to electrolyte disturbances, pseudo-membranous colitis, toxic megacolon and, rarely, death.

Clinical manifestations of C difficile can range from an asymptomatic carrier state to mild CDI to severe, fulminant, life-threatening infection.

How antibiotics affect the gut

Can probiotics prevent AAD?

Many factors, including drug dose, route of administration, absorption, and host inactivation, dictate the intensity of antibiotic effects on the gut microbiota. The normal microflora acts as a barrier against colonisation of potentially pathogenic microorganisms and against overgrowth of already present opportunistic microorganisms.

Antibiotics such as broad-spectrum b-lactams, glycopeptides and fluoroquinolones that act on anaerobes are most commonly linked to AAD. Mild cases have no established therapy, and are customarily treated with discontinuation of the antibiotic, supportive care, and dietary changes. However, serious cases often require bed rest, intravenous fluids, and additional antibiotics such as metronidazole or vancomycin, and may relapse in almost 25% patients.

The core benefit of probiotics is exercised by contributing to the maintenance of a balanced microbiota and therefore by creating a favourable gut environment.

Furthermore, probiotics support the health of the GI tract and the immune system.

The rationale for the use of probiotics is based on the assumption that AAD results from the disruption of the commensal gut microbiota caused by antibiotic therapy.

A recent review by Goodman et al (2021) found that probiotics are effective for preventing AAD. Probiotics are defined as live micro-organisms that, when administered in adequate amounts, confer a health benefit on the host.

Several studies have shown that probiotics improve the microbial balance of the host and reduce colonisation by pathogenic bacteria.

They can be delivered orally, are thought

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January 2022 | Vol. 22 No. 1 www.medicalacademic.co.za

to adhere to target GI epithelium and are stable in acid and bile.

Several mechanisms are proposed to contribute to the protective effect of probiotics against AAD. Antibiotics are known to disrupt the complex balance of gastrointestinal microbiota, allowing colonisation by pathogenic organisms such as C. difficile.

Probiotics are believed to temporarily colonise the gut, producing bactericidal acids and peptides, and competing for nutrients and epithelial adhesion.

Several species of the Lactobacillus genus are acid producing, lower environmental pH, and secrete exotoxins that inhibit pathogenic bacterial growth and inhibit binding of enterotoxins to gut epithelium, suggesting that probiotics may be the panacea (a solution or remedy for all difficulties or diseases) to AAD. The team conducted a systematic review and meta-analysis of randomised controlled trials to evaluate existing evidence for the use of probiotics in preventing AAD in adults.

Forty-two studies (n=11 305 participants)

were included in this review. The pooled analysis suggests that co-administration of probiotics with antibiotics reduces the risk of AAD in adults by 37%.

Efficacy and safety are strain specific According to Goodman et al, subgroup analyses comparing high and low dose of the same probiotic demonstrated a positive protective effect, and only certain species, mainly of the Lactobacillus and bifidobacterial genera, were found to be effective. Studies with a low baseline AAD risk did not show any difference in risk but studies with moderate or high baseline AAD risk demonstrated a significant risk reduction. 3 Lactobacillus reuteri recently renamed Limosilactobacillus reuteri (L. reuteri) is a Gram-positive bacterium that naturally inhabits the gut of mammals. First described in the early 1980s, it has been safely used in infants and adults to manage of GI symptoms such as gut infections, Helicobacter pylori eradication, AAD, constipation inflammatory bowel syndrome, inflammatory bowel disease, and colorectal cancer.4 It can reduce abdominal pain in infantile

colic, the functional abdominal discomfort in children, and it can decrease crying due to necrotizing enterocolitis in preterm neonates and can improve gut motility and chronic constipation as demonstrated in infants.4 L. reuteri can colonise different human body sites, including primarily the GI tract.

It adheres to the intestinal epithelium, producing proteins able to bind with the mucus, making it tough for pathogen microorganisms to enter, and thereby remodelling the balanced composition of gut microbiota.

Moreover, L. Reuteri produces antimicrobial molecules and promotes the development and the functionality of regulatory T cells, strengthening the gut barrier, and decreasing the microbial translocation from the intestinal lumen to the tissue.

Choosing an appropriate probiotic is challenging The choice of an appropriate probiotic is multi-factored, based on the mode and type of disease indication and the specific efficacy of probiotic strain(s), as well as product quality and formulation.

Conclusion In conclusion, L. reuteri plays a key role in maintaining a balanced microbiota gut composition. Many clinical trials have proved the safety, efficacy, and tolerance of this probiotic in preventing and treating numerous GI disorders, ranging from diarrhoea to constipation. Its efficacy and safety in the prevention of AAD has also been shown, leading researchers to conclude the probiotics may be the solution to AAD.

References Cai J, Zhao C, Du Y, et al. Comparative efficacy, and tolerability of probiotics for antibiotic-associated diarrhea: Systematic review with network metaanalysis. EUG Journal, 2018.

Goodman C, Keating G, Georgousopoulou E, Hespte C and Levett K. Probiotics for the prevention of antibiotic-associated diarrhoea: a systematic review and meta-analysis. BMJ Open, 2021.

Koldziej M and Szajewska H. Lactobacillus reuteri DSM 17938 in the prevention of antibioticassociated diarrhoea in children: protocol of a randomised controlled trial. BMJ Open, 2017.

Sniffen JC, McFarland LV, Evans CT, and Goldstein EJC. Choosing an appropriate probiotic product for your patient: An evidence-based practical guide. PLOSOne, 2018.

Walk ST and Young VB. Emerging Insights into Antibiotic-Associated Diarrhea and Clostridium difficile Infection through the Lens of Microbial Ecology. Interdisciplinary Perspectives on Infectious Diseases, 2008. SF

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SF | ONCOLOGY

January 2022 | Vol. 22 No. 1 www.medicalacademic.co.za

Global cancer figures

According to the 2021 GLOBOCAN report, which include data from 185 countries, the global cancer burden is expected to increase to 28.4 million cases – a 47% rise from 2020. The biggest increase is predicted for developing countries.

I

n 2020 an estimated 10 million people died as a result of cancer.

Female breast cancer surpassed lung cancer as the most commonly diagnosed cancer.

An estimated 2.3 million (11.7%) new cases were reported.

This was followed by: • Lung cancer 11.4%

• Colorectal cancer 10% • Prostate cancer 7.3% • Stomach cancer 5.6%

Cancer deaths Lung cancer is the leading cause of death in men, followed by prostate and colorectal cancer. In women, breast cancer is the most commonly diagnosed cancer and

In 2019 cancer was the first or second leading cause of death before the age of 70 in 112 countries

the leading cause of death, followed by colorectal and lung cancer.

The top five leading causes of cancer deaths were: _ Lung cancer 18% _ Colorectal cancer 9.4% _ Liver cancer 8.3% _ Stomach cancer 7.7% _ Breast cancer 6.9%

Reference Sung H, Ferlay J, Siegel RL et al. Global Cancer Statistics 2020: GLOBOCAN estimates of the incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 2021. SF

Save the Date

11-13 February European Society for Medical Oncology Summit Africa Cape Town

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Early identification of PAH is critical to improving patient outcome.1,2,3

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Early identification and intervention is key to changing the course of pulmonary arterial hypertension.⁵

5 Ambrisentan 5 mg; 10 mg

S4 Reg. No. 52/7.1.3/0604.602, 52/7.1.3/0605.603. Ambrisentan 5 mg, 10 mg. Each film-coated tablet contains Ambrisentan 5 mg; 10 mg respectively.

For full prescribing information, refer to the Professional Information approved by the medicines regulatory authority.

References: 1. Brown L, et al. Delay in Recognition of Pulmonary Arterial Hypertension: Factors Identified From the REVEAL Registry. Chest Volume 140, Issue 1, July 2011, Pages 19-26. 2. Armstrong I et al. The patient experience of pulmonary hypertension: a large cross sectional study of UK patients. BMC Pulmonary Medicine (2019) 19:67. 3. Farber H, et al. Five-Year Outcomes of Patients Enrolled in the REVEAL Registry. CHEST 2015; 148(4): 1043 - 1054. 4. Vachiéry JL, Galiè N, et al. AMBITION Study Group. Initial combination therapy with ambrisentan + tadalafil on pulmonary arterial hypertension-related hospitalization in the AMBITION trial. J Heart Lung Transplant. 2019 Feb;38(2):194-202. doi: 10.1016/j.healun.2018.11.006. 5. J Simon R Gibbs, National Pulmonary Hypertension Centres of the UK and Ireland. Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Heart. 2008 Mar; 94 Suppl 1:i1-41. doi: 10.1136/hrt.2007.132118.

CIPLA MEDPRO (PTY) LTD. Co. Reg. No. 1995/004182/07. Building 9, Parc du Cap, Mispel Street, Bellville, 7530, RSA. Website: www.cipla.co.za Customer Care: 080 222 6662. [790304252a]

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Thinking beyond HbA1c: managing CV risk in patients with T2DM Diabetes is often oversimplified as a ‘sugar’ problem. However, over time we have learned that diabetes affects multiple organs such as the brain, the kidneys, and the heart. The good news is that we have developed various treatments aimed at improving glycaemic control in these patients, resulting in improved outcomes.1

T

his is according to Dr Nqoba Tsabedze, Academic Head of Cardiology at the University of the Witwatersrand, and Clinical Head of Cardiology at the Charlotte Maxeke/ Johannesburg Academic Hospital.

Dr Tsabedze presented a webinar entitled Thinking beyond HbA1c: managing CV risk in patients with T2DM, hosted by Specialist Forum and sponsored by Eli Lilly.1 Globally, the prevalence of T2DM continues to rise. In 2017, an estimated 424.9 million people were living with diabetes. This number is expected to increase to 628.6 million by 2045.2

CV risk in patients with T2DM Although T2DM is often described in terms of a glucose pathology, many patients with the disease die as a result of cardiovascular disease (CVD).3,4 To reduce these patients’ CV burden, a number of management strategies have been developed, noted Dr Tsabedze.

Current guidelines place a greater focus on patient-related issues such as CVD.1 The risk of CVD depends on the duration of T2DM. Dr Tsabedze stressed that T2DM is not a ‘single-point event’, but rather a condition that unravels over time.1 The risk of atherosclerotic CVD (ASCVD) is accelerated in individuals with metabolic syndrome (eg hypertension, central obesity and dyslipidaemia). By the time they are diagnosed with T2DM, they have a significant risk of ASCVD and after eight to ten years of living with T2DM, present with coronary heart disease.1,5

Management of T2DM Management of T2DM is multi-pronged and should be based on shared decisionmaking between the clinician and patient.

An effective management plan should incorporate a thorough assessment of key patient characteristics and factors that may impact the choice of treatment.6,7 Key patient factors include: _ Current lifestyle _ Comorbidities (eg heart failure [HF], ASCVD, chronic kidney disease [CKD]) _ Clinical characteristics (eg HbA1c, weight) _ Issues such as motivation and depression _ Cultural and socioeconomic context.

Specific factors that impact the choice of treatment include: _ Individualised HbA1c target _ Impact on weight and hypoglycaemia _ Side effect profile medication _ Complexity of regimen (eg frequency and mode of administration) _ Access, cost and availability of medication.

CV trials Numerous CV trials have been conducted aimed at improving outcomes for patients with T2DM who are at high risk of CVD. According to Dr Tsabedze, the two therapies that have shown the best CV benefits include glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose transport protein 2 inhibitors (SGLT2i).1 He highlighted the following SGLT2i studies: _ The Empagliflozin, CV Outcomes, and Mortality in T2DM study: Patients with T2DM at high risk for CV events who received empagliflozin as compared with placebo, had a lower rate of the primary composite CV outcome and of death from any cause when the study drug was added to standard care.8 _ Dapagliflozin and CV Outcomes in T2DM: In patients with T2DM who had or were at risk for ASCVD, treatment with dapagliflozin resulted in a lower rate of CV death or hospitalisation for HF.9 He highlighted the following GLP-1RA studies: _ Liraglutide and CV Outcomes in T2DM: In the time-to-event analysis, the rate of the first occurrence of death from CV causes, nonfatal myocardial infarction (MI), or nonfatal stroke among patients with T2DM was lower with liraglutide than with placebo.10 _ Semaglutide and CV Outcomes in Patients with T2DM: In patients with T2DM who were at high CV risk, the rate of CV death, nonfatal MI, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo.11 _ Dulaglutide and CV Outcomes in T2DM: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with

T2DM with either previous CVD or CV risk factors.12 _ Oral Semaglutide and CV Outcomes in Patients With T2DM: Major adverse CV events occurred in 3.8% in the oral semaglutide group and 4.8% in the placebo group. Results for components of the primary outcome were as follows: death from CV causes, 0.9% in the oral semaglutide group and 1.9% in the placebo group, nonfatal myocardial infarction, 2.3% and 1.9%, respectively and nonfatal stroke, 0.8% and 1%, respectively. Death from any cause occurred in 1.4% in the oral semaglutide group and 2.8% in the placebo group.13

Key messages _ Most antidiabetic drugs show a neutral effect on CV outcomes in people with T2DM who were at an increased risk for CV events14 _ Newer antidiabetic drugs are associated with a lower risk of CV events in adults with T2DM who were at high CV risk8-13 _ GLP-1 RA and SGLT2i are the recommended options for individuals with T2DM and established CVD15 _ SGLT-2is have shown consistent reductions in hospitalisation for HF and CKD outcomes, with benefits in terms of major CV events and all-cause mortality in some CV outcome trials (CVOTs)16 _ GLP-1 RAs reportedly reduced ASCVD events, as well as all-cause mortality in some CVOTs16 _ While both GLP-1 RAs and SGLT-2is have shown CV benefits in real-world studies as well, the prescription of these drugs appears to be still inadequate17-21 _ The mechanisms of action of SGLT2is and GLP-1 RAs on metabolic and possibly CV/renal outcomes might be complementary22,23 _ Patients often exhibit multiple needs in terms of glucose and weight control and protection of organ damage (eg heart, brain, kidney), and this requires combination therapy with both SGLT-2is and GLP-1RAs.22,24 References available on request. SF

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*3-component MACE in REWIND (nonfatal stroke, nonfatal myocardial infarction, or death).

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Trulicity® proves powerful HbA1c reductions of up to -1.6% across a range of head-to-head clinical trials3

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Simple injection Hidden needle4 Once weekly3

ADA=American Diabetes Association; CV=cardiovascular; CVD=cardiovascular diseases; EASD=European Association for the Study of Diabetes; GLP-1 RA=glucagon-like peptide-1 receptor agonists; MACE=major adverse cardiovascular events; MI=myocardial infarction.

Reference: 1.Gerstein HC et al. Lancet. 2019 Jun 7. pii: S0140-6736(19)31149-3. doi: 10.1016/S0140-6736(19)31149-3. [Epub ahead of print]. 2.TBuse, J.B., Wexler, D.J., Tsapas, A. et al. 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 63, 221–228 (2020). https://doi.org/10.1007/s00125-019-05039-w 3.Trulicity® (dulaglutide once weekly) Trulicity® Professional Information , Eli Lilly and Company, Johannesburg, South Africa - 2020. 4.Trulicity® Instructions for use , Eli Lilly and Company, Johannesburg, South Africa - 2020

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Trulicity®. Reg No. 51/21.13/0344 Dulaglutide 1,5 mg/ 0,5ml solution for injection.

For more product information, please email us at: za_medinfo@lilly.com For full prescribing information, refer to the Professional Information approved by the medicines regulatory authority Eli Lilly (S.A.) (Pty) Ltd. Reg. No. 1957/000371/07 1st Floor, Golden Oak House, Ballyoaks Office Park, 35 Ballyclare Drive, Bryanston, Johannesburg Tel: +27 (11) 510 9300 © 2020 Eli Lilly and Company. All Rights Reserved.

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Adcock Ingram Limited. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021. Tel. + 27 11 635 0000. www.adcock.com 202103081091904