Knowledge Type: Clinical Articles

Antimicrobial resistance (AMR) continues to pose a serious threat to human health, as well as the health of animals and the environment. This week is World AMR Awareness Week, a global campaign run by the World Health Organization (WHO) to increase awareness and understanding of AMR.

The theme for this year’s campaign is “Preventing antimicrobial resistance together”. Tackling AMR must be a collaborative effort across sectors and around the world. While the healthcare sector is an important driver of antibiotic use, the quantity of antibiotics used in agriculture is significant. In the US, over 70% (by weight) of the antibiotics defined as medically important for humans are sold for use in animals.

As the prevalence of AMR increases, the availability of effective antimicrobial therapies becomes more limited. In 2019, it was estimated that 1.27 million deaths were directly attributable to bacterial AMR. Future predictions suggest that the annual death toll may eclipse cancer unless decisive action is taken.

Antimicrobial stewardship (AMS) is recognised as an important component of healthcare and is included in the National Safety and Quality Health Service (NSQHS) Standards. However, many AMS programs tend to focus on antibiotics, with antifungals often not receiving the same attention.

Antifungal stewardship shares many similarities with antibiotic stewardship. They both aim to optimise antimicrobial use, improve patient outcomes, reduce adverse sequelae, ensure the cost-effectiveness of therapy, and preserve the efficacy of currently available antimicrobials. However, there are additional issues that are unique to antifungal stewardship. Invasive fungal infections (IFI) tend to affect more complex patient populations, have high mortality rates, and the therapies are often associated with greater toxicity and higher costs.

The Australian Commission on Safety and Quality in Health Care has just released the 2023 Antimicrobial Use and Resistance in Australia (AURA) report. One of the key findings is that the use of systemic antifungals in Australian hospitals has increased annually since reporting began in 2017. Increasing use of antifungals is associated with a higher risk of resistance, especially with the azole class of antifungals.

One of the focus areas highlighted in the 2023 AURA report is antifungal drug susceptibility for common Candida species and Aspergillus fumigatus complex. These species are responsible for the majority of IFIs, so emerging AMR among these species will have significant clinical implications. While antifungal resistance among these species remains uncommon, the following findings were made:

• Small numbers of Candida group isolates, particularly Nakaseomyces (Candida) glabratus, were resistant to anidulafungin and micafungin;
• Four N. glabratus isolates that were echinocandin-resistant or had intermediate susceptibility were also resistant to azoles;
• Azole resistance among Candida tropicalis and N. glabratus may be emergent (around 8%);
• Voriconazole resistance among fumigatus complex was uncommon (<5%), which supports the use of this agent as first-line therapy for invasive aspergillosis pending the results of susceptibility testing.

Antifungal resistance

Resistance to antifungals can be intrinsic. For example, Aspergillus species and many other moulds are intrinsically resistant to fluconazole. Pathogenic fungi can also acquire resistance due to selection pressure exerted by antifungal drugs. The mechanism of this acquired resistance varies depending on the antifungal agent in question.

Azoles are some of the most commonly used antifungal agents. Their primary mechanism of action is thought to be inhibition of the cytochrome P450-dependent enzyme, lanosterol 14-alpha-demethylase. This enzyme plays a vital role in the production of ergosterol, an essential component of fungal cell walls. The disruption of ergosterol synthesis by azoles causes an increase in the permeability of the fungal cell wall, resulting in cell lysis and death.

Resistance to azoles is typically acquired due to:

• Increased efflux from the fungal cell (particularly for Candida species);
• Point mutations and promotor insertions in the CYP51A gene resulting in modification of the pathway for sterol biosynthesis (for fumigatus); and
• Overexpression of the drug target and efflux pumps (e.g. Cryptococcus neoformans).

In the case of echinocandins (e.g. anidulafungin, caspofungin, micafungin), mutations of the FKS1 gene are associated with resistance in Candida and Fusarium species. In the case of polyenes (e.g. nystatin and amphotericin B), resistance is caused by loss-of-function mutations in genes coding for ergosterol biosynthesis. This is particularly evident in Aspergillus and Candida species.

Antifungal stewardship

Khanina et al. (2020) conducted a study to develop an international expert consensus on a core set of metrics for antifungal stewardship.

Days of therapy and length of therapy were agreed metrics of consumption. These metrics were considered to be of high clinical relevance as they are not impacted by individualised drug dosing and can be utilised in both adult and paediatric settings. However, feasibility was considered to be low for these metrics as they require access to patient-level data, which can be labour-intensive.

In terms of quality metrics, there was high agreement for the performance and timeliness of fungal diagnostics and follow-up for suspected invasive mould and candida infections. The effectiveness of antifungal prophylaxis is important and can be measured by rates of IFI breakthrough. Respondents considered IFI-related mortality an ideal metric for measuring the impact of antifungals at a patient level. However, this metric was considered to have low feasibility. This is due to the complex characteristics of this patient group that necessitate a detailed case review to determine the cause of death. All-cause mortality was suggested as an alternative clinical outcome. Many of the usual clinical outcomes, such as length of stay and readmission, were also rated low for importance as multiple factors are likely to influence these metrics in such a complex patient group.

The findings of this study helped inform the development of the Antifungal National Antimicrobial Prescribing Survey (AF-NAPS). The AF-NAPS is now available for use in all Australian hospitals and can be accessed via the National Centre for Antimicrobial Stewardship website. It is used to assess guideline compliance and the overall appropriateness of antifungal therapies. Assessing appropriateness using the AF-NAPS is slightly different from other NAPS audits as guidelines are not available for all indications or may not be sufficient in all clinical scenarios. A rating of appropriate can be further broken down into optimal or adequate, and a rating of inappropriate is further classified as suboptimal or inadequate. Therapies may also be rated as ‘not assessable’ if there is a lack of documentation or the patient is too complex to categorise.

Future therapies

In comparison to antibiotics, there are few antifungal classes available. Therefore, emerging resistance to these agents poses a significant threat to human health. While new antifungal therapies are needed to address this issue, few novel antifungals have been developed in the past decade.

One newer method that has been investigated involves the use of nanoparticle formulations that attempt to improve the pharmacokinetic or pharmacodynamic properties of existing antifungals. Another potential strategy for immunocompromised patients is the use of monoclonal antibodies to provide passive immunisation.

There are also some novel antifungals in phase II/III clinical trials. Rezafungin was recently compared to caspofungin in a randomised double-blind, double-dummy phase III trial. Rezafungin is a next-generation echinocandin with a broad spectrum of activity. It is currently being developed for the treatment of candidaemia and invasive candidiasis and for prophylaxis against invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis species. One of the key potential benefits of rezafungin is its long half-life (around 133 hours), which allows an extended dosing interval. Results of this trial demonstrate that once-weekly rezafungin is non-inferior to daily caspofungin for the treatment of candidaemia and invasive candidiasis.

Dementia is a progressive disease, with non-cognitive symptoms emerging at a far greater rate as the person ages. Dementia causes significant emotional, psychological and structural turmoil for all involved, with a projected total of  150 million dementia sufferers by 2050, of whom 80% will have dementia of Alzheimer’s disease (Morales-de-Jesús et al., 2021). Because the beneficial effects of medications are very limited, there is an increasing move to non-pharmacological therapies to treat people with dementia (Gonzalez et al., 2015; Van Bogaert et al., 2016).

One notable example of this non-drug approach is reminiscence therapy (RT) which was originally proposed by Robert N. Butler, an American geriatric psychiatrist, in 1963. (Tanaka et al., 2007)

Reminiscence therapy is a psycho-social programme which seeks to re-establish a self-image through the re-connection with and importing of memories and experiences from a person’s past life, thereby creating a contemporary sense of worthiness, well-being and life coherence. (Klever, 2013) Hence, this therapy seeks to place a memory anchor in the past so as to bolster and redevelop the person’s sense of contemporary worth. (Kelly & Ahessy, 2021)   

As defined by Woods et al. (2005) “Reminiscence Therapy (RT) involves the discussion of past activities, events and experiences with another person or group of people, usually with the aid of tangible prompts such as photographs, household and other familiar items from the past, music and archive sound recordings.”

How RT is implemented:

 The RT program for older patients with dementia can involve 10 weekly sessions, each lasting 60 minutes and, in some research, is led by a psychologist. The sessions are adapted to the personal and cognitive capacities of the patients.   In each session, all of the stages of life are engaged with using different topics.

A Spanish program employed the same structure for each session. First, each member of the group was welcomed, then the topic for the session was announced.

Session topics can include childhood experiences, favourite foods, favourite travel destinations earlier in life, important personal events (marriage, birth of children, work achievements, etc.), significant historical events during the person’s life (the moon landing, the assassination of JFK, the life of Queen Elizabeth II, or other culturally relevant milestones).    

The patient is actively encouraged to share these memories with the group.

The group leader provides and nurtures an inclusive, non-judgemental environment which will encourage openness in dialogue and thereby add to each person’s sense of value, worth and dignity. The facilitator’s role is vital. They seek to reduce the use of negative memories and emotions and, instead, enhance interpersonal relationships and a positive sense of self. The facilitator should seek to import positive memories and feelings from the past and re-anchor them in the present, thereby promoting personal identity. (Gonzalez et al., 2015; Lök et al., 2019)

Intended benefits:

The intended benefits of RT are multi-layered and affect dementia patients differently.

For example, Cotelli et al. (2012) reported that RT yielded improvement in mood, well-being, behaviour, a better quality of life (QoL) for both the patient and their caregivers and a reduction in depressive states. Also, an improvement in autobiographical memory was reported. Notwithstanding these benefits, the authors lamented that (at that time) only a small number of trials had been conducted, and they were of poor quality.

Saragih et al. (2022) have proposed that the improved QoL from RT is due to a variety of factors. These include:

• Happiness when people with dementia recall their past life;
• A sense of social support due to interactions with peers within the group;
• The sharing of similar experiences with other people;
• An elevated self-confidence; and
• An improved sense of belonging.

More recently, a Cochrane review by Woods et al. (2018) reported that RT showed “some positive effects on people with dementia in the domains of QoL, cognition, communication and mood.” Enhanced self-esteem and improved socialisation capacity from RT has been reported by Liu et al. (2021).

Of particular note was research showing the positive impact of music and photographs in mild-to-moderate Alzheimer’s disease patients. They showed improvements in depression, QoL, social functioning and reduced behavioural and psychological symptoms of dementia (BPSD). (Cuevas et al., 2020)

These improvements may be due to improved brain blood flow, notably in the frontal lobe (Tanaka et al., 2007), which is responsible for “high-order cognitive abilities such as working memory, inhibitory control, cognitive flexibility, planning, reasoning, and problem solving.” (Cristofori et al., 2019)

Importantly, RT has also been shown to provide some positive benefits “on well-being, self-esteem, daily functioning and caregiver burden”. (Yan et al. 2023)

Barriers to implementation and how barriers are addressed and overcome.

A major barrier to implementation of RT is a lack of consistency in therapy presentation, duration of therapy, training and supervision of facilitators, academic skills of facilitators, as well as feedback to presenting staff.    (Macleod et al., 2021) Poor planning time, a lack of appropriate management support, and poor staff motivation are also barriers. (Van Bogaert et al., 2016)

To remediate this problem, a standardised training program is recommended which is measured against objective external criteria facilitating improvements in knowledge and techniques. Importantly, there needs to be a theoretical framework that underpins the group RT program. (Macleod et al., 2021)

It is important to note that the Royal Commission into Aged Care Quality and Safety included testimonials in support of the merits of RT. (Tracey & Briggs, 2018)

Other barriers include gender and age, which can be predictors of the RT outcomes. Pot et al. (2010) reported that relatively severely depressed women show better treatment outcomes, perhaps because women are more receptive to the ‘emotional sharing’ involved in RT and that the “creative components of this preventive course may be better appreciated by females.”

Hence, facilitators need to be mindful that men and women respond differently, which suggests that a “men’s shed” approach may be more beneficial, because men and women socially interact and unveil themselves differently. (Barbagallo et al., 2023)

The degree of dementia is also a barrier to RT implementation. Residents showing severe dementia symptoms do not benefit in the domains of depression, neuropsychiatric presentations, cognitive function, independence or QoL due to “extreme shrinkage of the cerebral cortex and hippocampus … .” (Saragih et al., 2022) Hence, these patients may need to be excluded from group RT sessions as they may be more disruptive than contributory, secondary to agitation and aggression. (Müller-Spahn, 2003)

Finally, the cost of running RT sessions may be too expensive for some Residential Aged Care Facilities. To alleviate this problem, digital RT can be deployed. This approach “allows multiple users to participate in a therapy simultaneously. Moreover, digital RT offers convenience, such as for uploading personal materials and presenting individual triggers of personal memories.” (Moon & Park, 2020)

The fungal kingdom encompasses a range of diverse species, including moulds, yeasts, and mushrooms. It has been estimated that there are between 2.2 and 3.8 million species of fungi. All fungi are eukaryotic organisms as their cells have a membrane-bound nucleus. Eukaryotic cells are typically much larger and more complex than prokaryotic cells, such as bacteria.

Nomenclature

Fungi are categorised using a hierarchical taxonomic system. The levels of this hierarchy (from broadest to most specific) are domain, kingdom, division, class, order, family, genus, and species. Table 1 demonstrates this classification system, using Candida albicans as an example.

Table 1. Taxonomic hierarchy of Candida albicans

Level	Example
Domain	Eukarya
Kingdom	Fungi
Division	Ascomycota
Class	Saccharomycetes
Order	Saccharomycetales
Family	Saccharomycetaceae
Genus	Candida
Species	albicans

An individual species is referred to by its genus and species names. i.e. Candida albicans is a species of yeast that belongs to the genus Candida and the species albicans. The scientific convention is to capitalise all names in this hierarchy, with the exception of species name; italics are used for the genus and species.

The naming of fungal species has undergone significant changes in recent years. Nomenclature continues to evolve as new technologies improve species identification, allowing historical naming errors to be addressed. One of the most substantial naming changes occurred in 2013, where the dual naming of pleomorphic fungi was abandoned in favour of a “one fungus, one name” strategy.

Pleomorphic fungi are species that can exist in two different morphs, i.e. an anamorph (asexual) stage and a teleomorph (sexual) stage. Pichia kudriavzeveii is a good example of this issue. This species is generally considered safe and is widely distributed in the environment and used in the production of some fermented foods. However, this organism was later found to be the teleomorph of the known human pathogen Candida krusei. The currently accepted name for this species is P. kudriavzeveii.

Yeasts and moulds

Fungi that may be pathogenic to humans can occur as yeasts, moulds, or a combination of both forms.

Yeasts are microscopic single-celled fungi that typically reproduce by a process known as budding or blastogenesis. This is a type of asexual reproduction whereby a bud forms on the parent cell and grows before separating to become a new yeast cell that is genetically identical to the parent cell.

In comparison, moulds grow in multicellular filaments known as hyphae. Reproduction is primarily through the production of spores, which can be disseminated through the air or via water, animals or objects. Spores are more resistant to stressors such as high temperatures and some cleaning methods. A comparison of other features of these two forms can be seen in Table 2.

Table 2. A comparison of mould and yeast

	Mould	Yeast
Cell	Multicellular	Predominantly unicellular
Shape	Filamentous	Round or oval
Appearance	Fuzzy, range of possible colours	White
Hyphae	Microscopic filaments called hyphae	Can form multicellular structures called pseudo-hyphae
Typical habitat	Damp or dark conditions	Widely dispersed in nature (e.g. on plants and fruits, soil), surface of skin and intestinal tract of warm-blooded animals.
Ideal growth temperature	28℃	37℃
Reproduction	Spores (sexual or asexual)	Mostly via mitosis (asexual)
Health risks	Allergic reactions, respiratory problems, mycotoxins, infections.	Infections
Source of energy	Moulds produce hydrolytic enzymes that degrade biopolymers into simpler carbohydrates that can then be absorbed by the mould cell.	Alcoholic fermentation (produces ethanol and carbon dioxide as end products of carbohydrate metabolism)
Examples	Aspergillus fumigatus, Fusarium spp.	Candida albicans, Candida auris

Some fungi may be categorised as dimorphic. Dimorphic fungi have a yeast (or yeast-like) phase and a mould (filamentous) phase. Thermally dimorphic fungi produce a mould form between 25°C and 30°C and a yeast form at 35°C to 37°C. This allows the fungi to exist as an environmental mould and then convert into a parasitic yeast at mammalian body temperature. Dimorphic species that are considered pathogenic to humans include:

• Sporothrix schenckii (worldwide distribution with a higher prevalence in tropical and temperate regions, can cause sporotrichosis);
• Histoplasma capsulatum (found in soils with high organic content and undisturbed animal droppings, illness more likely to occur in people who are immunocompromised);
• Paracoccidioides brasiliensis (recently published Australian case of infection);
• Blastomyces dermatitidis (not typically found in Australia); and
• Coccidioides immitis (can cause Valley fever, endemic to parts of America).

Fungal infections

Many fungal species are part of the normal human microbiota. However, infections can occur that range from superficial infections to invasive infections that are life-threatening. The majority of invasive fungal infections are caused by candidiasis (around 70%); cryptococcosis and aspergillosis are also important causes.

Risk factors for developing an opportunistic fungal infection include:

• Long-term immunosuppressive therapy;
• Acquired immunodeficiency syndrome (AIDS);
• Diabetes;
• Significant burns;
• Neoplastic disease; and
• Chronic respiratory disease.

The World Health Organization (WHO) has compiled a list of priority fungal pathogens. This is a catalogue of 19 fungal species deemed the greatest threat to human health, as shown in Table 3.

Table 3. WHO fungal priority pathogens

Pathogens	Type	Comment
Critical group
Cryptococcus neoformans	Yeast	Opportunistic; spread via inhalation. Cerebral cryptococcosis is life-threatening.
Candida auris	Yeast	Intrinsically resistant to most antifungals. Can cause life-threatening invasive candidiasis.
Aspergillus fumigatus	Mould	Spread via inhalation; emerging resistance to azoles
Candida albicans	Yeast	Mucosal infections or life-threatening invasive candidiasis. Low rates of antifungal resistance.
High priority group
Nakaseomyces glabrata (Candida glabrata)	Yeast	Commensal; increasingly common cause of invasive candidiasis
Histoplasma spp.	Dimorphic	Spread via inhalation; histoplasmosis more likely in immunocompromised hosts
Eumycetoma causative agents	Various genera	Deep tissue infection caused by fungi in soil and water that enter the body through breaks in the skin.
Mucorales	Mould	Fungal group causing mucormycosis, particularly in immunocompromised hosts, poorly controlled diabetes and skin and soft tissue injuries.
Fusarium spp.	Mould	Invasive fusariosis is life-threatening; innate resistance to many antifungals.
Candida tropicalis	Yeast	Commensal; can cause life-threatening invasive infection.
Candida parapsilosis	Yeast	Commensal; can cause life-threatening invasive infection. Concern in neonatal ICUs.
Medium priority group
Scedosporium spp.	Moulds	Opportunistic; can cause life-threatening invasive scedosporiosis.
Lomentospora prolificans	Mould	Opportunistic; can cause invasive lomentosporiosis in immunocompromised patients.
Coccidioides spp.	Dimorphic	Found in the Americas; can cause life-threatening invasive coccidioidomycosis.
Pichia kudriavzeveii (Candida krusei)	Yeast	Opportunistic; mucosal infections or invasive candidiasis.
Cryptococcus gattii	Yeast	Spread via inhalation; global distribution; invasive disease is life-threatening.
Talaromyces marneffei	Dimorphic	Spread via inhalation; endemic to parts of Asia; invasive talaromycosis is life-threatening
Pneumocystis jirovecii	Yeast-like	Previously known as P. carinii; global distribution; can cause life-threatening pneumonia, particularly in immunocompromised. Drug prophylaxis highly effective.
Paracoccidioides spp.	Dimorphic	Endemic to Central and South America; inhalation or penetration of skin by spores; paracoccidioidomycosis is life-threatening.

Fungal contamination

Fungal contamination in indoor spaces can take the form of:

• Microbial volatile organic compounds (MVOCs) – fungi (and bacteria) can release a range of volatile compounds, including alcohols, ketones, aldehydes, and sulfur and nitrogen compounds. These compounds can cause local irritation of the upper respiratory tract, nose, throat, eyes, and skin;
• Mycotoxins – toxic substances produced by fungi. The most toxic mycotoxins include aflatoxins, ochratoxin A, zearalenone, trichotecenes, and fumonisins. These metabolites may be produced by various moulds, particularly Aspergillus and Fusarium Toxicity may be acute (e.g. skin irritation, diarrhoea, hepatotoxicity, nephrotoxicity) or chronic (e.g. cancer, impaired immune responses, congenital abnormalities); and
• Fungal spores and fragments of mycelia – may cause allergic reactions. Inhalation of fungal spores can cause disease, particularly in immunocompromised people.

As fungi are ubiquitous, they can pose a risk in healthcare settings. Risk factors for the proliferation of fungi within these areas include poor ventilation, dampness, and surfaces that are porous or damaged. Fungi can be introduced to a space through the air and also by personnel. Healthy adults carry a significant load of fungi, particularly on the toes and heel. However, exposed areas such as the head, neck and eyebrows may also harbour high levels. Fungi can also be introduced into a manufacturing space or drug room via packaging. Cardboard packaging is a particular concern as it can serve as a food source for cellulolytic fungi. Examples of cellulolytic fungi are Aspergillus, Chaetomium, Trichoderma, Penicillium, and Alternaria.

Fungal contamination of pharmaceutical products can lead to product spoilage. Depending on the species, ingredients in the formulation may be utilised by fungi as a source of energy. Fungi can use substances ranging from simple sugars through to complex aromatic molecules. The resulting chemical modification within the pharmaceutical product may lead to reduced therapeutic effect, reduced palatability, or pH changes that promote bacterial proliferation. For example, Aspergillus and Penicillium spp. can produce proteinases and peptidases that break down compounds in pharmaceuticals such as gelatine.

Fungal contamination also poses a risk of infection. The extent of this risk is dependent upon several factors, including:

• The type of organisms present;
• The number of organisms present;
• Route of administration for the contaminated product; and
• Patient factors.

Risk assessment

The response to fungal contamination of a pharmaceutical will depend upon whether the product is intended to be sterile or non-sterile. Any contamination of a sterile product is unacceptable. However, a risk assessment may be undertaken for non-sterile products to determine the potential for patient harm. This would include consideration of the species identified, the number of organisms present, and the type of pharmaceutical product in question.

Case studies:

Fungal contamination has led to product recalls in Australia. For example, in 2016, the Therapeutic Goods Administration (TGA) initiated a recall of one batch of acetazolamide tablets. This was due to the identification of Penicillium and Aspergillus in the bottles.

However, one of the most serious cases of fungal contamination occurred in the United States in 2012. A preservative-free methylprednisolone acetate injection was contaminated with various fungal species, primarily the mould Exserohilum rostratum. Of the more than 13,000 people potentially exposed to this contaminated product, 753 people developed infections related to the contamination and 64 deaths were recorded. Infections included fungal meningitis, localised spinal or paraspinal infections, and infections in peripheral joint spaces. This incident was later traced back to several sterility assurance failures. The significant morbidity and mortality associated with this incident highlights the importance of contamination control.

Contamination control

Areas used for pharmaceutical manufacturing or dose manipulations must be cleaned appropriately to control microbial growth. Cleaning should be regular and in accordance with a documented and validated procedure.

Decontamination processes may be divided into the following categories:

• Cleaning – physically removes dirt and grime that may harbour microbes and inactivate disinfectants;
• Sanitisers – used on surfaces to reduce the number of microorganisms, but they do not necessarily eliminate microorganisms;
• Disinfectants – used on hard surfaces to destroy or irreversibly inactivate fungi, viruses, and bacteria. These agents are not necessarily effective against spores;
• Sporicidal agents – destroy fungal and bacterial spores;
• Sterilisation – a process that destroys all microbial forms, including resistant forms such as fungi and bacterial spores; and
• Antiseptics – considered separately as they are used on living tissue to inhibit or destroy microorganisms.

Disinfectants:

Alcohol-based disinfectants, such as ethyl alcohol and isopropyl alcohol, are commonly used to disinfect surfaces. They are effective against fungi as well as bacteria and viruses. However, they are typically not effective against spores.

Isopropyl alcohol is often used in concentrations of 60-90%, with 70% being most common. The water content is important as it enhances penetration into the cell wall and acts as a catalyst in denaturing the proteins of cell membranes. The addition of water also slows evaporation of the alcohol, increasing its contact time with the surface. Once the concentration of isopropyl alcohol drops below 50%, its effectiveness as a disinfectant significantly falls. On the other hand, concentrations exceeding 90% lead to almost immediate coagulation of surface or cell wall proteins. This creates a protective layer around the microbe that prevents the alcohol from entering the cell, thereby reducing its effectiveness.

Alcohol-based cleaning products may be described as “denatured”. This denotes the inclusion of an additive that makes the product unpalatable and unfit for consumption. Other products may be labelled as “sterile alcohol”. This is a certification that the alcohol meets guideline requirements reflecting the highest standards of purity (i.e. filtered, gamma-irradiated, packaged within a cleanroom environment, etc.). Sterile alcohol is commonly used in cleanrooms, e.g. to wipe down working surfaces.

There are some disadvantages of alcohol-based disinfectants. Firstly, as they are not sporicidal and cannot penetrate protein-rich material, they are generally not appropriate for sterilising medical and surgical materials. Also, they are flammable, and their vapours can be irritating.

Sporicides

Fungal spores are more resistant to decontamination efforts than vegetative cells. However, bacterial spores are considered the most difficult to control. Many disinfectants are considered sporostatic, but not actively sporicidal against all spores. Examples include phenols, cresols, chlorhexidine, and quaternary ammonium compounds.

Sporocidal agents include glutaraldehyde, sodium hypochlorite, iodine/iodophors, hydrogen peroxide, and peracetic acid. Many of these agents can be corrosive to hard surfaces and may also present a health hazard to staff that come into contact with them. Therefore, decontamination programs may use sporicidal agents less frequently than other complementary processes.

For a decontamination process to be effective, it must achieve complete distribution and penetration of the treated area. It is also important that the product has sufficient contact time and is used at the specified concentration and environmental conditions for optimal efficacy.

 

Lower urinary tract symptoms (LUTS) are common in men and increase with age. These symptoms can be classified as either voiding symptoms or storage symptoms. Voiding symptoms are often related to prostate enlargement. This may present with urinary hesitancy, weak stream, and incomplete bladder emptying. Storage symptoms are typically due to overactivity of the detrusor muscle and may present as nocturia and urinary urgency or frequency. Therapies for LUTS in men include alpha blockers, 5α reductase inhibitors, and antimuscarinics.

Alpha blockers

The selective alpha blockers available for the management of LUTS are alfuzosin, prazosin, silodosin, and tamsulosin. These agents reduce the resistance to urinary flow through the blockade of presynaptic alpha₁ receptors, which causes smooth muscle relaxation in the bladder neck and prostate. Prazosin also blocks postsynaptic alpha₁ receptors, which can result in vasodilation.

There are three subtypes of alpha₁ receptors: alpha_1A, alpha_1B, and alpha_1D. Alfuzosin and prazosin are non-subtype selective. Tamsulosin is considered subtype selective as it has a ten-fold greater affinity for alpha_1A and alpha_1D subtypes than alpha_1B. Silodosin is also subtype selective as it has a 162-fold higher affinity for alpha_1A compared to alpha_1B. Greater affinity at alpha_1A receptors may be advantageous as these receptors are primarily located in the prostate and bladder. In comparison, alpha_1B receptors are primarily located in the cardiovascular system.

Common adverse effects include first-dose hypotension, orthostatic hypotension, dizziness, nasal congestion, urinary urgency, and fatigue. Cardiovascular effects are more likely to occur with prazosin.

A meta-analysis suggests that the efficacy of selective alpha blockers for the management of LUTS is similar. Interestingly, this analysis found little to no difference in the incidence of cardiovascular adverse events for silodosin compared to alfuzosin or tamsulosin. However, silodosin was associated with a higher rate of sexual adverse events (e.g. retrograde ejaculation and anejaculation).

5α reductase inhibitors:

Dutasteride and finasteride inhibit 5α reductase. This enzyme is responsible for converting testosterone to dihydrotestosterone, a potent stimulant of prostate growth. Therapy with a 5α reductase inhibitor reduces prostate size and improves urinary flow rate.

Dutasteride inhibits both type 1 and type 2 isoenzymes, while finasteride only inhibits the type 2 isoenzyme of 5α reductase. Following two weeks of continuous dosing, dutasteride can reduce dihydrotestosterone levels by around 90%. In comparison, long-term finasteride dosing is associated with a 70% reduction in circulating dihydrotestosterone levels. However, evidence suggests that there are not any major differences between the two agents for reduction of prostate size, symptom improvement, urinary flow rate, or adverse effects.

Women who are pregnant or may become pregnant should avoid exposure to 5α reductase inhibitors as they are pregnancy category X drugs. They are associated with a potential risk of feminisation of the male foetus. As dutasteride and finasteride can be absorbed through the skin, women should not handle capsules that are leaking or tablets that have been broken or crushed. Finasteride tablets are coated, which prevents contact with the active ingredient during normal handling of whole tablets. Patients must refrain from donating blood while taking a 5α reductase to prevent administration to a pregnant female. As dutasteride has a long half-life (3 to 5 weeks), there is a recommended waiting time of at least six months after the last dose before blood donations can resume.

A fixed-dose combination of dutasteride plus tamsulosin is available. The combination of alpha blocker and 5α reductase inhibitor is more effective in reducing disease and symptom progression in benign prostatic hyperplasia and also decreases the risk of acute urinary retention.

Antimuscarinics

Antimuscarinic medications can be used to manage storage symptoms. Detrusor contraction is mediated via the action of acetylcholine on the M₃ receptor subtype. Therefore, medications that are M₃ selective (e.g. darifenacin and solifenacin) may be associated with less anticholinergic adverse effects than non-selective antimuscarinics.

Potential adverse effects include urinary retention, dry mouth, constipation, dyspepsia, blurred vision, dry eyes, tachycardia, arrhythmia, dizziness, memory impairment, confusion, and insomnia. Adverse effects tend to be dose-related. Older individuals are typically more sensitive to anticholinergic adverse effects, and the lowest effective dose should be used.

An antimuscarinic may be combined with an alpha blocker if storage and obstructive symptoms exist.

An overview of medications used in the management of LUTS is shown in Table 1.

Table 1. Medications for LUTS in men

Medication	Use	Usual oral dose	Comments
Alpha blockers
Alfuzosin	Voiding symptoms	10mg daily	Swallow whole after food
Prazosin		0.5-2mg twice daily	Larger effect on blood pressure
Silodosin		8mg daily	Swallow whole with food
Tamsulosin		400mcg daily	Swallow whole
Antimuscarinics
Darifenacin	Storage symptoms	7.5-15mg daily	Swallow whole
Oxybutynin		2.5-5mg 2 or 3 times daily	Also available as a patch that is changed every 3-4 days
Solifenacin		5-10mg daily
Tolterodine		1-2mg twice daily
5α reductase inhibitors
Dutasteride	Voiding symptoms	500mcg daily	Swallow whole
Finasteride		5mg daily
Combinations
Tamsulosin + dutasteride	Voiding symptoms	400mcg+500mcg daily	Swallow whole 30 minutes after meal

 

Overweight and obesity are the second leading risk factors for ill health and death in Australia, second only to tobacco use. Excess weight is linked to 30 diseases, including some cancers, cardiovascular disease, and type 2 diabetes. It is responsible for 8.4% of the total disease burden and contributed to around 16,400 deaths in Australia in 2018.

The body mass index (BMI) is one tool that can be used to measure general adiposity. The BMI can be quickly calculated by dividing a person’s weight (kg) by their height (m). Some general classifications of weight according to BMI are shown in Table 1.

Table 1. Classification of weight according to BMI

BMI (kg/m2)	Classification
< 18.5	Underweight
18.5 to 24.9	Healthy
25 to 29.9	Overweight
≥ 30	Obese
30 to 34.9	·       Class I
35 to 39.9	·       Class II
≥ 40	·       Class III

Some caution is required when interpreting BMI figures in individuals. The BMI is intended to be used in conjunction with other assessments to evaluate an individual’s health status appropriately. However, based on the latest available data, 67% of all Australian adults are living with overweight or obesity and 31% are obese. In addition, 60% of men and 66% of women have a waist circumference that indicates a substantially increased risk of metabolic complications.

Studies suggest that even modest weight loss (5-10% body weight) is associated with a significant improvement in overall health in people with obesity. While lifestyle modification is the cornerstone of weight loss strategies, this may be supplemented with weight loss medications in some cases. Medicines that are currently approved in Australia solely for the purpose of weight loss are orlistat, phentermine, naltrexone with bupropion, and liraglutide.

Orlistat

Orlistat is registered for the treatment of obese patients with a BMI of at least 30 in conjunction with a mildly hypocaloric diet. Orlistat may also be used in overweight patients with a BMI of at least 27 if other risk factors are present.

Orlistat is a selective and reversible inhibitor of gastric and pancreatic lipase activity. Lipases are important in the digestion of dietary fat, catalysing the hydrolysis of ester bonds in triglycerides. This leads to the production of free fatty acids and monoglycerides that can be absorbed. This process is impaired in the presence of orlistat, and the undigested triglycerides are not absorbed. At recommended doses, orlistat prevents the absorption of around 30% of dietary fat

Orlistat is available as 120mg tablets, which can be taken up to three times daily with meals. Doses should be administered during or up to one hour after the meal. Doses should be omitted if a meal is skipped or contains no fat.

As systemic exposure to orlistat is minimal, adverse effects are predominantly gastrointestinal in nature. Owing to its mechanism of action, orlistat leads to increased fat in the stool, which can produce diarrhoea and faecal urgency or incontinence. These effects can be minimised by reducing the fat content of the diet.

A vitamin supplement should be considered as orlistat may reduce the absorption of fat-soluble vitamins. If a supplement is used, it should be taken at least two hours before or after an orlistat dose.

Phentermine

Phentermine is a sympathomimetic amine that acts as an appetite suppressant. It is a central nervous system stimulant with major effects on the noradrenergic and dopaminergic nervous systems. The appetite suppressant effects are thought to be mediated through the hypothalamus.

Due to its stimulatory effect on the sympathetic nervous system, phentermine has a number of contraindications, including:

• Pulmonary artery hypertension;
• Existing heart valve abnormalities or heart murmurs;
• Moderate to severe arterial hypertension;
• Cerebrovascular disease;
• Severe cardiac disease including arrhythmias, advanced arteriosclerosis;
• Hyperthyroidism;
• Agitated states or a history of psychiatric illnesses including anorexia nervosa and depression;
• Glaucoma;
• History of drug/alcohol abuse or dependence; and
• Concomitant treatment with a monoamine oxidase (MAO) inhibitor or within 14 days following their administration.

Common adverse effects include central nervous system (CNS) overstimulation, which may present as insomnia, restlessness, nervousness, or agitation. Cardiovascular effects are also common and may include arrhythmia, tachycardia, and hypertension.

Phentermine is administered as a once-daily dose. Due to its stimulatory effects, doses should be taken in the morning to prevent insomnia. Phentermine has a limited role in the long-term management of obesity and is recommended for short-term treatment.

Naltrexone with bupropion

Naltrexone is available in a fixed-dose combination with bupropion for the management of weight in adults with an initial BMI of 30 kg/m² or more. It may also be initiated in adults with a BMI of 27 kg/m² or more if a weight-related comorbidity is present, such as type 2 diabetes, dyslipidaemia, or controlled hypertension. It should be used as an adjunct to a reduced-calorie diet and increased physical activity.

The precise mechanism of action that leads to weight loss is not completely understood for this combination. Naltrexone is a mu-opioid antagonist that may block the effects of endogenous opioids. The pro-opiomelanocortin (POMC) cells of the hypothalamus produce melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin, an endogenous opioid. Alpha-MSH activates the melanocortin-4 receptor (MC4R), which leads to reduced appetite and increased energy expenditure. Beta-endorphin inhibits the activity of POMC cells by binding to the inhibitory mu-opioid receptor.

Bupropion is a weak inhibitor of dopamine and noradrenaline reuptake. In vitro, it has been shown to enhance POMC cell production and release of alpha-MSH and beta-endorphin. When taken with naltrexone, the beta-endorphin inhibitory feedback on POMC cells is blocked. Therefore, this combination has synergistic effects on POMC signalling, producing greater effects on weight loss than either agent on its own.

Treatment is usually initiated with one tablet in the morning. The dose is then escalated over the following four weeks to a maintenance dose of two tablets twice daily.

Due to the opioid-antagonist properties of naltrexone, this medication should not be used in patients who are currently dependent on chronic opioids or patients in acute opioid withdrawal.

Liraglutide

Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue. Other medications in this class are dulaglutide and semaglutide. In Australia, these medications are all registered for the treatment of type 2 diabetes, while liraglutide is also registered for weight management.

Glucagon-like peptide-1 has a range of actions in the body, including the glucose-dependent stimulation of insulin secretion, inhibition of glucagon secretion, delayed gastric emptying, and inhibition of food intake. As the half-life of GLP-1 is less than two minutes, modification of the peptide is required to allow an appropriate dosing interval. Liraglutide has an amino acid sequence that is 97% homologous to endogenous human GLP-1. Modifications of the liraglutide molecule slow its absorption and make it more stable against metabolic degradation. This increases its half-life to 13 hours following subcutaneous administration.

Liraglutide is administered once daily with an initial dose escalation period to improve tolerability. Gastrointestinal adverse effects are common, with up to 50% of patients experiencing nausea or vomiting at the start of therapy. Other common adverse effects include diarrhoea, constipation, dyspepsia, and injection site reactions. Hypoglycaemia may also occur, particularly if the patient is also taking insulin or a sulfonylurea.

Comparative efficacy

Singh et al. (2020) conducted a meta-analysis to investigate the effect of anti-obesity medications on weight loss and other cardio-metabolic parameters. Medications compared included orlistat, phentermine plus topiramate, naltrexone plus bupropion, and liraglutide. In this study, phentermine was administered as part of a fixed-dose combination with topiramate. This product is not registered for use in Australia.

The meta-analysis found that the weight-lowering potential of these agents was greatest for phentermine plus topiramate, followed by liraglutide, then naltrexone plus bupropion, and lowest for orlistat. Compared to placebo, the weight reduction for each agent is shown below (all p < 0.00001):

• Phentermine plus topiramate 9.77 kg (95% CI: 11.73 to 7.81);
• Liraglutide 5.25 kg (95% CI: 6.17 to 4.32);
• Naltrexone plus bupropion 4.39 kg (95% CI: 5.05 to 3.72); and
• Orlistat 3.07 kg (95% CI: 3.76 to 2.37).

While the weight-lowering potential of orlistat is considered modest, its simple dosing and better tolerability are potential advantages.

These agents may have other benefits in addition to their effect on weight, such as glycaemic control and effects on lipid profiles.

Effects on glycaemic control noted by Singh et al. include:

• Orlistat
  • Associated with a reduction in HbA_1c of 0.4% and fasting blood glucose of 18mg/dl.
  • In patients with impaired glucose tolerance, orlistat was associated with a reduced rate of progression to diabetes (3.0% compared to 7.6%).
• Phentermine plus topiramate
  • Associated with a 0.4% reduction in HbA_1c in patients with diabetes.
  • A significant reduction in the required dose of antihyperglycaemic medications was also seen.
  • The SEQUEL trial showed a 78.7% reduction in the development of diabetes in patients with pre-diabetes or metabolic syndrome.
• Naltrexone plus bupropion
  • Change in HbA_1c ranged from no change to a 0.5% reduction in the COR trials.
  • No data was available on the rate of diabetes progression.
• Liraglutide
  • Associated with a reduction in HbA_1c of 0.33% to 1.85% in patients with type 2 diabetes (doses up to 1.8mg).
  • Associated with a reduction in HbA_1c of 0.2% to 0.9% in patients without diabetes.

The overall effect of these medicines on cardiovascular outcomes is uncertain. However, Singh et al. observed the following effects:

• Orlistat
  • Small but significant reductions in total cholesterol and low-density lipoprotein (LDL)
  • Small but significant reduction in systolic blood pressure
• Phentermine plus topiramate
  • Reduction in triglycerides and increased high-density lipoprotein (HDL), but no effect on HDL
• Naltrexone plus bupropion
  • Small but significant reduction in triglyceride and LDL and a small increase in HDL.
  • Unfavourable effects on systolic blood pressure and heart rate.
• Liraglutide
  • Reduced triglycerides but no significant improvement in LDL or HDL.
  • Small but significant reduction in systolic blood pressure plus a small increase in heart rate.

 

The Australian Commission on Safety and Quality in Healthcare (ACSQHC) has just released the revised Hip Fracture Clinical Care Standard (2023). This publication provides guidance on pain management, time to surgery, mobilisation, and prevention of future fractures.

Almost 19,000 new hip fractures are thought to occur in Australia each year. These fractures typically occur in older individuals after a fall. This is often a life-changing event, significantly impacting future mobility and independence. In addition, one in four people who experience a hip fracture die within the following 12 months.

Key changes included in the revised standard include:

• The reduction in recommended time to surgery from 48 hours to 36 hours. This time is from the first presentation to a healthcare facility, even if transfer to another facility is required;
• The addition of statements to include delirium, nutrition, and frailty in assessments and management. Assessments for cognitive impairment are aligned with the Delirium Clinical Care Standard; and
• Changes to the quality statements regarding analgesia. This includes the use of nerve blocks and other changes to better align with the care described in the Opioid Analgesic Stewardship in Acute Pain Clinical Care Standard.

Much of these updates have been informed by the Australian and New Zealand Hip Fracture Registry (ANZHFR) data. An interesting statistic from the ANZHFR Annual Report 2023 is that only 31% of patients presenting to Australian hospitals with a hip fracture were discharged on a bisphosphonate, denosumab, or teriparatide. Upon admission, 13% of patients were receiving therapy with one of these agents.

This issue is addressed in ‘Quality statement 6 – minimising the risk of another fracture’. Prior to discharge from hospital, patients should receive a falls and bone health assessment and management plan. When clinically appropriate, bone protection medicines are an important measure to reduce the risk of subsequent fractures.

Bone protection medicines include the following three categories:

1. Bisphosphonates reduce bone resorption by binding to bone hydroxyapatite, particularly at sites with active resorption. As osteoclasts resorb bone, the bisphosphonate in the bone is released and impairs the ability of osteoclasts to continue bone resorption. There are a number of different bisphosphonates available, and they may be administered orally or parenterally.
2. Denosumab is a monoclonal antibody. It also reduces bone resorption by inhibiting osteoclasts. However, it achieves this by binding to the RANK (receptor activator of nuclear factor-kappa B) ligand to prevent activation of the RANK receptor. This leads to decreased formation and activity of osteoclasts. Denosumab is administered subcutaneously on a six-monthly schedule.
3. Teriparatide is the active fragment of human parathyroid hormone (PTH). The physiological actions of PTH include the regulation of bone metabolism, renal reabsorption of calcium and phosphate, and the intestinal absorption of calcium. Teriparatide has the same effects on the bones and kidneys as PTH and results in the promotion of bone formation and increased bone mineral density (BMD). Teriparatide is administered subcutaneously on a daily basis.

A summary of available bone protection medicines is shown in Table 1.

Table 1. Summary of bone protection medicines

Drug	Route	Typical dose	Administration instructions
Bisphosphonates
Alendronate	Oral	70mg weekly	· Swallow tablet whole in the morning with a full glass of plain water at least 30 minutes before food or drink. Remain upright during this time and until after you eat. · Antacids, calcium, iron or mineral supplements must not be taken within 30 minutes of alendronate.
Risedronate	Oral	5mg daily	· Swallow tablet whole in the morning with a full glass of plain water at least 30 minutes before food or drink. Remain upright during this time and until after you eat. · Enteric-coated tablets (i.e. Actonel EC®) may be taken with or without food but the patient must still remain upright for 30 minutes after dose. · Antacids, calcium, iron and mineral supplements must not be taken within 2 hours of risedronate.
		35mg weekly
		150mg monthly
Zoledronic acid	IV	5mg annually	· Supplemental calcium and vitamin D are recommended after a low-trauma hip fracture. · Studies mostly used a vitamin D loading dose (50,000-125,000 IU orally or IM) 2 weeks prior to infusion; then maintenance calcium (1,000-1,500mg daily) and vitamin D (800-1,200 IU daily).
Other
Denosumab	SC	60mg every 6 months	· Adequate calcium and vitamin D supplementation is required to reduce the risk of hypocalcaemia. · Studies have used calcium 1,000 mg daily and at least 400 IU vitamin D daily.
Teriparatide	SC	20mcg daily	· Recommended lifetime maximal duration of 24 months

The ACSQHC advises that the revised clinical care standard maintains the same scope and goal as the original standard. Facilities that are currently using the 2016 Hip Fracture Clinical Care Standard may continue to use this for up to 12 months, but should transition to the updated version as soon as possible.

Chronic obstructive pulmonary disease (COPD) is estimated to affect around 5% of people over 45 years of age, yet accounts for over half of the disease burden due to respiratory conditions. This progressive condition is characterised by persistent airflow limitation due to small airways disease and alveolar destruction. This can be caused by abnormal inflammatory responses arising from the long-term exposure to noxious particles or gases. Cigarette smoking is the most common risk factor, although environmental factors such as dust, gas, chemical fumes, smoke or air pollution may contribute. Genetic factors may also play a role. For example, alpha-1 antitrypsin deficiency is a genetic disorder that is associated with an increased risk of emphysema.

Smoking cessation remains the most important intervention to limit lung damage in COPD. However, pharmacotherapy is also used to relieve symptoms and improve quality of life. Medications that may be used for the management of stable disease include:

• Short-acting bronchodilator therapy, e.g. a short-acting beta₂ agonist (SABA);
• Long-acting bronchodilator monotherapy, e.g. a long-acting beta₂ agonist (LABA) or long-acting muscarinic antagonist (LAMA);
• Long-acting bronchodilator dual therapy, e.g. LABA plus LAMA combination therapy; or
• Triple therapy, i.e. LABA, LAMA plus inhaled corticosteroid.

Acute exacerbations are managed with inhaled bronchodilators, although systemic corticosteroids may also be required. The use of antibiotics in this setting is not as well-defined. It is known that not all acute exacerbations have an infective cause. Non-infective causes of exacerbations include environmental pollutants as well as serious conditions such as heart failure and pulmonary embolism.

Studies suggest that infectious causes are involved in 88% of acute exacerbations of COPD. Respiratory viruses are commonly implicated. Viruses that are often identified in these patients include influenza A, rhinovirus, and respiratory syncytial virus (RSV). Features suggestive of a bacterial infection include increasing dyspnoea along with increasing sputum volume and either a change in sputum colour or purulence.

The benefits of antibiotics need to be balanced against their potential harms. Antibiotic use is associated with adverse effects such as diarrhoea and yeast infections, while also increasing the risk of Clostridioides difficile infection. Reducing the inappropriate use of antibiotics is also important to address the issue of antibiotic resistance. The most recent AURA (Antimicrobial Use and Resistance in Australia) Report indicates that COPD has some of the highest rates of inappropriate antibiotic use, with 65% of prescriptions considered non-compliant with guideline recommendations.

The Therapeutic Guidelines advise that the benefit of antibiotics for acute exacerbations is related to disease severity. A Cochrane meta-analysis demonstrated that, while antibiotics may have some benefits in the management of acute exacerbations, these effects are often small. In addition, the benefits are inconsistent for some outcomes (such as treatment failure) and absent for other outcomes (including mortality and length of hospital stay) in most patient groups. However, for patients managed in the intensive care unit, antibiotics were associated with a strong beneficial effect.

If antibiotics are considered appropriate for an acute exacerbation of COPD, amoxicillin or doxycycline are the first-line options recommended by the Therapeutic Guidelines. A recent study further supports the use of antibiotics, particularly doxycycline, in this setting.

Doxycycline is a tetracycline antibiotic. The guidelines recommend a dose of 100mg daily for five days. Oesophageal irritation and ulceration can occur if the tablet or capsule adheres to the oesophagus. To reduce this risk, it is advised to administer tablets with adequate fluid and to ensure the patient remains upright for at least half an hour after each dose.

The guidelines recommend amoxicillin to be administered at a dose of 500mg three times daily or 1g twice daily for five days. Doses may be taken without respect to food, but should be spaced as evenly as possible.

Lack of response to these antibiotics may not always require a change to broader-spectrum therapy. Attention should be given to ensuring the patient is receiving appropriate inhaled bronchodilator therapy. Oral corticosteroids may also be required. Consideration of viral and non-infective causes of the exacerbation should also be considered and managed appropriately.

Erythropoiesis-stimulating agents (ESAs) are used to promote the production of erythrocytes. This medication group includes recombinant human erythropoietin (EPO) derivatives (e.g. epoetin alfa, epoetin beta, and epoetin lambda) and chemically modified forms of EPO (e.g. methoxy polyethylene glycol-epoetin beta and darbepoetin alfa).

Erythropoietin is a hormone that is primarily produced in the kidneys and is essential for regulating the production of erythrocytes. While EPO is constantly secreted at low levels, surges can occur when erythrocyte levels drop. The interstitial peritubular cells of the kidneys detect this relative hypoxia in the blood and respond by increasing EPO release.

Erythropoiesis-stimulating agents are indicated for use in conditions of impaired erythrocyte production, such as anaemia of chronic renal failure and chemotherapy-induced anaemia. They may also be indicated for use in patients with mild-to-moderate anaemia (haemoglobin 100–130 g/L) who are undergoing elective surgery with expected moderate blood loss and to support autologous blood collection before major elective surgery in patients with anaemia.

For patients with chronic kidney disease (CKD), ESAs can effectively manage anaemia and reduce the need for blood transfusions. However, patient response to these agents can vary significantly. Erythropoietin resistance occurs when target haemoglobin (Hb) levels cannot be met or increasingly higher ESA doses are required to maintain Hb targets.

Erythropoietin resistance is associated with a higher risk of death and cardiovascular events in patients with CKD. While the reasons for this have not been fully elucidated, EPO resistance is associated with increased blood pressure, endothelial stress, and a prothrombotic state. Anaemia itself is also strongly associated with cardiovascular issues due to reduced tissue oxygenation, which can lead to tachycardia, vasodilation, increased cardiac workload, and left ventricular hypertrophy. Therefore, it is important to recognise factors that may contribute to EPO resistance and optimise anaemia management in this patient group.

Some potential causes of EPO resistance include:

• Iron deficiency;
• Infection and inflammation;
• Malnutrition;
• Hyperparathyroidism; and
• Inadequate dialysis.

Iron deficiency is the most common cause of EPO resistance in dialysis patients. Iron deficiency may be considered absolute or functional. There are many factors that may contribute to absolute iron deficiency in people with CKD, including gastrointestinal losses, reduced gastrointestinal iron absorption, frequent blood draws, and the impact of dietary restrictions. For patients undergoing haemodialysis, some residual blood loss occurs, which can become significant over time.

In the case of functional iron deficiency, total body iron stores are sufficient, but their bioavailability is reduced. This may be related to systemic inflammation, which results in increasing levels of hepcidin. Hepcidin is an iron regulatory protein that impairs iron transport. Hepcidin levels may rise in CKD due to reduced elimination via the kidneys, increased levels of inflammatory cytokines, and in response to reduced EPO levels.

Malnutrition is a significant issue for patients with CKD. The risk of malnutrition is elevated in this population due to decreased appetite and nutrient intake, intestinal malabsorption, metabolic and endocrine derangements, inflammation, increased catabolism, and dialysate losses. The role of poor nutrition in the development of anaemia is well established, with deficiencies of folic acid, vitamin B12, and iron all contributing. However, studies suggest that a significant effect of malnutrition on EPO resistance is related to malnutrition-inflammation syndrome.

Malnutrition-inflammation syndrome describes the nutritional changes seen in protein-energy wasting as well as the inflammatory changes seen due to uremic toxins and oxidative stress. This inflammatory state may contribute to EPO resistance by reducing EPO production and its effects on erythropoiesis. Inflammation and infection can also increase hepcidin production, which is associated with functional iron deficiency. Evidence suggests that even low-level inflammation can contribute to ESA resistance. Therefore, testing C-reactive protein may be beneficial to detect minor asymptomatic elevations in this inflammation marker that could be significant.

Chronic kidney disease is a common cause of secondary hyperparathyroidism. This condition is a hallmark of end-stage renal disease (ESRD) and is associated with EPO resistance. As CKD progresses, the synthesis and secretion of PTH increases. Rao et al. (1993) first demonstrated an association between higher parathyroid hormone (PTH) levels and greater bone marrow fibrosis in patients with a poor EPO response. There is also evidence to suggest that high levels of PTH increase the osmotic fragility of erythrocytes. These two factors may combine to reduce erythrocyte production as well as their survival.

In CKD, secondary hypoparathyroidism may be driven by hypocalcaemia and hyperphosphataemia. As phosphate complexes with calcium, high levels of serum phosphate lead to reduced levels of ionised calcium. Reduced levels of this physiologically active form of calcium trigger the release of increasing quantities of PTH. Longstanding secondary hyperparathyroidism can lead to tertiary hyperparathyroidism, where the parathyroid glands become unresponsive to plasma calcium levels and autonomously produce high levels of PTH in the presence of hypercalcemia. High levels of phosphate, active vitamin D, and PTH also increase the release of fibroblast growth factor 23 (FGF23). The FGF23 hormone plays a significant role in CKD-related mineral and bone disorders. Evidence suggests that FGF23 may also be important in the development of ESA resistance.

Inadequate dialysis has been shown to increase the risk of ESA resistance in patients receiving dialysis. While the mechanism for this has not been fully elucidated, adequate haemodialysis in CKD patients is associated with lower ESA doses. One study demonstrated that extending the duration of haemodialysis by one hour may reduce the EPO requirement by around 2,000 IU per week.

Lower ESA doses are associated with significant clinical benefits as well as improved cost-effectiveness of treatment. Addressing reversible causes of EPO resistance is important to ensure the optimal use of ESAs. This may include optimisation of iron supplementation, haemodialysis modality, nutritional intake, and other comorbidities.

 

The thyroid gland produces three hormones, thyroxine (T4), triiodothyronine (T3), and calcitonin. Thyroxine is the main hormone produced by the thyroid gland. While triiodothyronine is the more active form, the majority of this hormone is produced peripherally via the breakdown of thyroxine.

Thyroid hormones play an important role in development, growth, and metabolism. In adults, the main effects of thyroid disorders are metabolic. Hypothyroidism may present with fatigue, weight gain, cold intolerance, and depression. Symptoms of hyperthyroidism may include heart palpitations, hyperactivity, increased sweating, heat hypersensitivity, fatigue, increased appetite, weight loss, insomnia, and frequent bowel movements.

The production of thyroid hormones is regulated by thyroid stimulating hormone (TSH), produced by the anterior pituitary. Thyroid stimulating hormone is under negative feedback control by the circulating levels of free thyroid hormone and under positive control by hypothalamic thyrotropin-releasing hormone (TRH). The production of thyroid hormones is also affected by the extrathyroidal deiodination of T4 to T3. This can be affected by nutrition, other hormones, illness, and medications.

There are many medications that can affect thyroid function. Amiodarone is interesting in that it can cause both hypothyroidism and hyperthyroidism. The incidence of amiodarone-induced thyroid dysfunction is estimated to be around 14-18%. Studies have wide variations in the reports of thyroid dysfunction, which may be related to geographic differences in iodine deficiency. The incidence of amiodarone-induced thyrotoxicosis (AIT) has been reported to vary between 1% in some studies up to 23% in others. Similarly, the reported incidence of amiodarone-induced hypothyroidism (AIH) varies between 1% and 32%. Areas with a higher level of iodine deficiency have a higher incidence of AIT, while AIH is more common in areas without iodine deficiency.

The incidence of iodine deficiency in Australia differs by region. Tasmania has the highest proportion of people with urinary iodine levels below 50μg/L (denoting mild deficiency). This is thought to be due to lower levels in the soil and, therefore, lower levels in the foods produced locally.

Amiodarone

Amiodarone is a commonly used antiarrhythmic agent. It is indicated for the treatment of severe tachyarrythmias such as Wolff-Parkinson-White Syndrome; supraventricular, nodal and ventricular tachycardias; atrial flutter and fibrillation; and ventricular fibrillation.

The chemical structure of amiodarone and its main metabolite are also very similar to T3. Amiodarone and its metabolite demonstrate the ability to inhibit the transport of thyroid hormones across the plasma membrane, and the metabolite may also antagonise the effects of T3 at the molecular level.

Each molecule of amiodarone contains two iodine atoms, which accounts for around 37% of its molecular weight. A 200mg amiodarone tablet contains approximately 75mg of organic iodine. From this, around 6mg of free iodine is released following deiodination during drug metabolism. However, the recommended dietary intake for iodine is only 150 micrograms per day for adults. The amount of iodine released from a tablet also greatly exceeds the upper level of intake of 1,100 micrograms per day for adults.

When a normal thyroid gland is exposed to large quantities of iodine, the Wolff-Chaikoff effect is initiated. This autoregulatory phenomenon reduces thyroid activity in response to increased plasma iodide. This effect normally lasts for a few days before the normal synthesis of thyroid hormones resumes (referred to as escape from the Wolff-Chaikoff effect). However, in some patients, this escape from the Wolff-Chaikoff effect may not be achieved, and hypothyroidism results.

Alternatively, iodine overload can result in the Jod-Basedow phenomenon or iodine-induced thyrotoxicosis. This typically occurs in people with an underlying thyroid condition such as multinodular goitre or Graves’ disease and is more likely in areas of iodine deficiency. In these individuals, excess iodine from amiodarone therapy leads to uncontrolled overproduction of thyroid hormones.

Amiodarone can also cause thyroid dysfunction via mechanisms unrelated to iodine overload. Amiodarone causes inhibition of deiodinases, enzymes involved in the activation and inactivation of thyroid hormones. Amiodarone may also have a direct cytotoxic effect, resulting in apoptosis of thyroid cells.

Risk factors for amiodarone-induced thyroid dysfunction include advanced age, female sex, and a daily amiodarone dose exceeding 200mg.

Hypothyroidism

Amiodarone-induced hypothyroidism is more likely to arise in the first year of amiodarone treatment. The prevalence is thought to reduce after this time as the thyroid gland adapts to the increased thyroid intake.

Compared to AIT, this type of thyroid dysfunction is more likely to occur in:

• Areas with sufficient iodine intake;
• Women (ratio of women to men is 1.5:1);
• Patients that are older; and
• Earlier stages of therapy.

Amiodarone-induced hypothyroidism can affect patients with no previous history of thyroid dysfunction. However, the development of long-term AIH is more likely in patients with pre-existing thyroid disease and positive antithyroid antibodies.

Hyperthyroidism

Amiodarone-induced thyrotoxicosis is not as common as AIH. However, AIT can have serious complications for patients taking amiodarone due to worsening of their underlying cardiac condition. Patients with AIT have a significantly higher risk of experiencing major cardiovascular events, with one study demonstrating a 2.7-fold increased risk. The elderly and those with a left ventricular ejection fraction <45% are at particular risk.

Compared to AIH, this type of thyroid dysfunction is more likely to occur in:

• Areas of iodine deficiency;
• Men (male to female ratio of 3:1); and
• Later in therapy (typically between 4 months and 3 years after initiation of amiodarone).

There are two main types of AIT:  type 1 (related to the high iodine content of amiodarone) and type 2 (related to direct damage of thyroid cells). However, a mixed type has also been described in which both mechanisms are involved, and features of both may be present.

Type 1 AIT

This condition develops in patients with pre-existing thyroid disease. Increased intake of iodine in these patients is thought to promote the synthesis and release of increasing quantities of thyroid hormone to produce clinically evident hyperthyroidism.

Type 2 AIT

This condition is more likely to develop in a patient without pre-existing thyroid disease. Type 2 AIT is a destructive thyroiditis mediated by amiodarone and its metabolite. The resulting tissue damage leads to increased release of previously synthesised thyroid hormone.

The clinical presentation of AIT may include weight loss, reduced heat tolerance, fatigue, muscle weakness, increased frequency of bowel movements, oligomenorrhea, anxiety, depression, and palpitations. However, for some patients, the reappearance of anginal pain, atrial fibrillation or tachycardia may be the only indication.

Monitoring and treatment

Monitoring of thyroid function (ultrasensitive TSH assay) is recommended before starting amiodarone therapy, regularly during treatment, and for several months after discontinuation.

Identification of thyroid dysfunction in a patient taking amiodarone raises the question of whether the therapy should be continued. An individual assessment of the benefits and risks of continuing or ceasing therapy is required.

In many cases, amiodarone therapy can be continued for patients who have developed AIH. Hypothyroidism can be treated in these cases with levothyroxine, with the dose adjusted according to TSH levels.

Treatment decisions for AIT are more complex. This form of thyroid dysfunction may not respond to therapy discontinuation and can even develop after discontinuation of amiodarone. Type 1 AIT is treated with antithyroid therapy (e.g. carbimazole, propylthiouracil) and type 2 AIT is treated with high-dose glucocorticoids. Thyroidectomy may be required if no response is achieved after four to six weeks.

When considering discontinuation of amiodarone therapy, it is important to remember that amiodarone and its metabolite have long half-lives. With chronic dosing, the half-life of amiodarone may range from 14-110 days and 60-90 days for the metabolite. Therefore, the effects of ceasing amiodarone are gradual. In addition, discontinuing amiodarone in patients with AIT could actually exacerbate symptoms of thyrotoxicosis. This is due, in part, to the effects of amiodarone on blocking the peripheral conversion of T4 into the more active T3.

 

What is rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that affects the joints and can damage other body systems, including the skin, eyes, lungs, heart, and blood vessels. Unlike the wear-and-tear damage of osteoarthritis, RA is an autoimmune disorder where the immune system attacks the joints. This can result in painful swelling, bone erosion and joint deformity.

Medications include:

• Nonsteroidal anti-inflammatory drugs (NSAIDs);
• Steroids;
• Conventional disease-modifying anti-rheumatic drugs (DMARDs); and
• Biological agents.

What are biological agents?

Biologics are a newer class of DMARDs that may slow or stop inflammation. In people with RA, the immune system mistakenly takes aim at its own tissues, leading to high levels of cytokines that can cause joint inflammation and pain. Biologics work by blocking these substances to diminish the immune response and reduce inflammation, pain and joint damage.

Biologics are made from living cells and tend to work quicker than conventional DMARDs. Conventional DMARDs suppress the overall immune system, whereas biologics block specific parts of the immune system. Biologics are more complex than conventional DMARDs and must be administered parenterally.

According to the Therapeutic Guidelines, biological disease-modifying anti-rheumatic drugs (bDMARDs) are used by specialists if remission is not achieved or significant disease activity persists after trialling conventional DMARDs. Biologicals are usually used in combination with conventional DMARDs.

The guidelines provide the following usual dosages for first-line bDMARDs (listed in alphabetical order):

• Abatacept 500 to 1000 mg intravenously, as a single dose at 0, 2 and 4 weeks, and thereafter every 4 weeks; OR
• Abatacept 125 mg subcutaneously, once weekly; OR
• Adalimumab 40 mg subcutaneously, every 2 weeks; OR
• Certolizumab pegol 400 mg subcutaneously, as a single dose at 0, 2 and 4 weeks, and thereafter 200 mg every 2 weeks; OR
• Certolizumab pegol 400 mg subcutaneously, as a single dose at 0, 2 and 4 weeks, and thereafter every 4 weeks; OR
• Etanercept 50 mg subcutaneously, once weekly; OR
• Golimumab 50 mg subcutaneously, every 4 weeks; OR
• Infliximab 3 mg/kg intravenously, as a single dose at 0, 2 and 6 weeks, and thereafter every 8 weeks; OR
• Tocilizumab 8 mg/kg intravenously, every 4 weeks; OR
• Tocilizumab 162 mg subcutaneously, once weekly.

If the response to the initial drug choice is inadequate, the guidelines advise that an alternative first-line bDMARD may be used.

Rituximab is reserved for when first-line bDMARD therapy has failed. The two doses (1g by intravenous infusion) are given two weeks apart. For patients who respond to this initial rituximab course, treatment may be repeated (usually after 6 to 12 months) depending on disease activity.

Different types of biological therapies:

All bDMARDs are associated with an increased risk of infections. The most common infections seen are upper respiratory infections, pneumonia, urinary tract infections, and skin infections. Patients should be advised to contact their doctor if they develop signs of an infection.

Patients should not receive live vaccines when taking biologics.

1. Tumour necrosis factor (TNF) inhibitors = adalimumab, certolizumab, etanercept, golimumab, infliximab

These agents bind to TNF alpha and inhibit its activity. TNF alpha is a pro-inflammatory cytokine produced by macrophages and lymphocytes.

Following initiation of a TNF inhibitor, improvements may be seen within two to four weeks, with further effects over the next three to six months. 

2. T-cell Co-stimulatory blockers

Abatacept (Orencia^®)

Abatacept is a fusion protein that binds to the CD80 and CD86 molecules on the surface of antigen presenting cells. This prevents the interaction of these molecules with CD28 found on T cells, thereby reducing the T cell response.

The onset of effect may be seen within 14 days, with continued improvement over the following 12 months. Discontinuation should be considered if there is no effect after three to four months.

3. B-Cell inhibitors

Rituximab (Rituxan^®)

Rituximab is a monoclonal antibody that binds to the CD20 molecule on the B cell surface, removing B cells from circulation. A single course of rituximab (two infusions of 1,000mg given two weeks apart) leads to a prompt reduction of B lymphocytes in the peripheral blood. This effect is prolonged, with recovery of B cell counts usually beginning six to nine months after completion of therapy.

The onset of action may be slower for rituximab than other bDMARDs, and effects may not be seen for up to three months after an infusion. However, the effects may last six months or longer following a single course.

Rituximab is associated with infusion reactions such as hives, itching, swelling, difficulty breathing, fever, chills and changes in blood pressure. These respond to slowing the infusion rate. Patients receive premedication with intravenous corticosteroids, paracetamol and an antihistamine before each dose.

Rituximab may also be associated with progressive multifocal leukoencephalopathy (PML), a severe and potentially fatal brain infection.

Angina, arrhythmias, heart failure and myocardial infarction, have also been reported in patients treated with rituximab.

4. Interleukin inhibitors

Interleukin-6 (IL-6)

Tocilizumab (Actemra^®)

Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors. IL-6 is a pleiotropic pro-inflammatory cytokine involved in various physiological activities, including T-cell activation, immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoiesis. Synovial and endothelial cells can also produce IL-6, leading to local production in joints affected by inflammatory processes.

The usual time to effect is around four to eight weeks.

Caution is required in patients with a history of intestinal ulceration or diverticulitis due to reports of gastrointestinal perforation. Other potential adverse effects include reduced platelet count, elevations in liver transaminases, increased lipid parameters, and neutropenia.

Interleukin-1 (IL-1)

IL-1 is another pro-inflammatory cytokine involved in the pathogenesis of RA. IL1 can cause degradation of cartilage and inhibit its repair. It also stimulates osteoclasts, leading to bone erosion.

Anakinra

Anakinra is an IL-1 receptor antagonist. It is administered as a subcutaneous injection, with a recommended dose of 100mg daily. The usual time to effect is around two to four weeks.

The most common side effects are injection site reactions which may present as erythema, itching, and discomfort. These usually resolve over one to two months, although patients with severe reactions may require discontinuation of therapy.

Anakinra is not available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of rheumatoid arthritis.