Knowledge Type: Clinical Articles

The tirzepatide (Mounjaro®) product information has been updated to include a warning of pulmonary aspiration in patients undergoing general anaesthesia or deep sedation.

Tirzepatide is indicated for the treatment of type 2 diabetes. It is a long-acting agonist of both the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Its action on the GLP-1 receptor stimulates insulin secretion in hyperglycaemic states, suppresses glucagon secretion, delays gastric emptying, and decreases appetite. Activation of GIP receptors enhances some of the effects of GLP-1 stimulation, particularly in regard to appetite. This dual mechanism significantly improves glycaemic control, insulin sensitivity, and lipid metabolism while reducing body weight.

Delayed gastric emptying

The effect of tirzepatide and other GLP-1 agonists on gastric emptying may increase the risk of aspiration during anaesthesia. Aspiration of regurgitated gastric contents into the lungs is a serious event that can lead to pneumonitis, aspiration pneumonia, or other lung injury. Patients taking a GLP-1 agonist may have high gastric volumes despite appropriate fasting before the procedure. During anaesthesia, the presence of food or fluid contents in the stomach is a major risk factor for aspiration.

Other GLP-1 agonists available in Australia are shown in Table 1. Dulaglutide and semaglutide are considered long-acting agents, and liraglutide is short-acting. While GLP-1 agonists were originally used in the management of type 2 diabetes, the expansion of indications and off-label use for weight loss has led to a significant increase in their use.

Table 1. GLP-1 agonists registered in Australia

Drug	Registered indication	Half-life (approx.)
Dulaglutide	Type 2 diabetes	4.7 days
Liraglutide	Weight loss Type 2 diabetes	13 hours
Semaglutide	Type 2 diabetes	7 days
Tirzepatide	Type 2 diabetes	5 days

A recently published study investigated the potential for semaglutide to increase residual gastric content (RGC) despite adequate preoperative fasting. Patients undergoing upper gastrointestinal endoscopy who had taken semaglutide within 30 days had their RGC compared to patients who had not taken semaglutide. The findings suggest that semaglutide increased the risk of elevated RGC almost five-fold.

The effect of GLP-1 agonists on gastric emptying is thought to be most pronounced at the beginning of therapy. Tachyphylaxis occurs with ongoing use, particularly in the case of long-acting agents. Evidence suggests that the dosing regimen may affect this, with intermittent dosing (as may occur when used for weight loss) showing a similar effect on gastric emptying to acute dosing.

It should be noted that delayed gastric emptying is often associated with diabetes, regardless of GLP-1 agonist use. In addition, many commonly prescribed medications can also slow gastric emptying. This includes opioids, proton pump inhibitors, anticholinergics, calcium channel blockers, and levodopa. Concomitant use of a GLP-1 agonist with another drug that slows gastric emptying may further increase the risk of aspiration during anaesthesia.

Managing therapy during the perioperative period

Holding medications that delay gastric emptying can help to reduce the risk of pulmonary aspiration. However, three to five half-lives are normally required to clear a drug from the body. This may not be practical for surgery scheduling, particularly when considering the long half-lives of many GLP-1 agonists. For example, semaglutide has a half-life of around one week. In addition, it may not be desirable to hold the medication for so long, given their clinical benefits on glucose control and cardiovascular health.

Further evidence is required to guide recommendations in this area. In patients with type 2 diabetes, the glycaemic benefits of continuing GLP-1 agonist therapy throughout the perioperative period may outweigh the potential issues related to delayed gastric emptying. They offer effective glycaemic control with a low risk of fasting hypoglycaemia. Therefore, continuing their use before surgery could potentially deliver cardiovascular benefits, improve wound healing, and avoid wound infections. However, the risk-benefit profile may not be the same when these agents are used for weight loss. Higher doses are used in the management of obesity, which may have a more pronounced effect on gastric emptying. In addition, patients may be more likely to use these agents intermittently, which could mitigate the development of tachyphylaxis.

The American Society of Anesthesiologists recommends that prescribers consider withholding the GLP-1 agonist for one dose before an elective procedure (i.e., hold on the day of surgery for daily dosing, hold for one week before surgery for weekly dosing). This advice remains the same regardless of the indication for the GLP-1 agonist. If holding the dose is not possible, they advise that ‘full stomach’ precautions should be implemented. The Australian and New Zealand College of Anaesthetists (ANZCA) highlights GLP-1 agonists as a risk factor and advises that gastric ultrasound can be used to mitigate risk and guide perioperative management. Other possible strategies to reduce the risk of aspiration include using a longer fasting duration and consideration of a prokinetic (e.g. metoclopramide or erythromycin).

Summary

Tirzepatide and GLP-1 agonists slow gastric emptying. A potential adverse event related to this effect is aspiration during anaesthesia or deep sedation, even in patients who have fasted according to standard recommendations.

The risk of aspiration is potentially higher in patients who have recently started a GLP-1 agonist, use intermittent dosing, or take another medication that delays gastric emptying. It is currently unclear when gastric emptying returns to normal after cessation of a GLP-1 agonist, and more evidence is needed to understand the potential role of withholding these agents during the perioperative period. ANZCA has recommended the use of gastric ultrasound as a means of assessing the aspiration risk of individual patients.

Bacillus Calmette and Guerin (BCG) is an attenuated strain of Mycobacterium bovis, the pathogen responsible for bovine tuberculosis. Calmette and Guérin cultivated this stable, non-virulent substrain during the development of their tuberculosis vaccine, which was first administered to humans in 1921. As there was no method of preserving viable mycobacterium at that time, BCG required continuous culture. By 1961, the original BCG strain had been serially passaged 1,173 times, resulting in the development of several daughter strains. These strains were then named after the manufacturer and place of origin.

As a result, BCG is not a well-defined pharmacological agent. Rather, it is a term applied to a pool of BCG strains that have acquired phenotypic and genotypic variations due to in vitro culturing in different laboratories under different conditions. These strains can be grouped as shown in Table 1.

Table 1. Groups of BCG substrains

Group	Description	Names
1	Early strains – closest genetically to original strain	BCG Russia BCG Moreau BCG Japan
2	Deletion of IS6110 gene upstream of phoP	BCG Sweden BCG Birkhaug
3	Established after 1931	BCG Glaxo BCG Prague BCG Danish
4	Late strains	BCG TICE BCG Frappier BCG Phipps BCG Connaught BCG Pasteur 1173

Comparison of substrains

The various substrains have noted differences in immunogenicity, antibiotic susceptibility, and adverse effects. Some studies suggest that these distinctions translate into only small differences in the efficacy of BCG vaccines against tuberculosis. However, head-to-head studies looking at different substrains in bladder cancer are limited. This makes it difficult to compare the clinical efficacy of different strains in this setting.

One study compared the in vitro anti-tumour effects of eight different strains. This study demonstrates that BCG Russia and BCG Connaught are the most effective in inhibiting cell proliferation and inducing cytokine production, while BCG Glaxo was the least effective.

Boehm et al. (2017) conducted a systematic review and meta-analysis to examine whether different BCG strains are associated with different clinical responses in bladder cancer. Their analysis demonstrated that BCG significantly reduced disease recurrence compared to chemotherapy and surgery. However, no BCG strain was found to be significantly superior in preventing disease recurrence.

Supply issues

In recent years, manufacturing issues have led to global shortages of BCG products. Australia currently has a shortage of OncoTICE® (BCG Tice), the Australian-registered BCG product for bladder irrigation. This long-term supply interruption is expected to continue until at least the end of December 2024.

The Therapeutic Goods Administration (TGA) has authorised the supply of an internationally registered alternative under Section 19A of the Therapeutic Goods Act 1989. The alternative product, VesiCulture BCG, is registered in Denmark. The package insert and product labelling is in English.

It is important to appreciate that the strengths of these two products are expressed differently. An OncoTICE vial contains 2-8 × 10⁸ colony-forming units (CFU), which may also be expressed as 500 million CFU. In contrast, the strength of VesiCulture is typically stated as 30mg per vial but may also be referred to as 2.5 x 10⁸ CFU.

In clinical trials, a standard dose is often defined as 120mg for the Danish strain and 5 × 10⁸ CFU for the TICE strain. This equates to four vials of VesiCulture or one vial of OncoTICE.

Some of the other key differences between VesiCulture and OncoTICE® are summarised in Table 2.

Table 2. Comparison of OncoTICE and VesiCulture (adapted from Link Communication 2023)

	OncoTICE®	VesiCulture
Strain	Tice BCG	BCG Danish strain 1331
Contents of one vial	500 million CFU (2-8 × 108 CFU)	30mg per vial (Approx. 2.5 x 108 CFU)
Pack size	One or three glass vials	Four glass vials
Dosage	Each instillation comprises 2-8 × 108 CFU (the contents of one reconstituted and diluted vial of OncoTICE suspended in 0.9% sodium chloride up to a total volume of 50 mL)	Normal dose (120 mg) = 4 reconstituted vials. The required dose is resuspended in 50 ml sterile preservative-free 0.9% sodium chloride.
Standard dose	1 vial	4 vials
Storage of reconstituted product	2 hours at 2-8 °C. Protect from light	Up to 4 hours at 2-8 °C. Protect from light

BCG Efficacy

The anti-tumour activity of BCG is thought to be related to local modulation of immune responses, leading to inflammation and the subsequent elimination of malignant cells. Interaction of BCG with urothelial cells may result in immunological effects, such as the induction of chemokines (e.g. interleukin-8), pro-inflammatory cytokines (e.g. granulocyte-macrophage colony-stimulating factor, tumour necrosis factor α, interleukin-6), and the upregulation of adhesion-molecule expression.

There are a number of conditions that should be met to improve the likelihood of treatment success with BCG. These include:

• The patient must be immunocompetent to ensure a robust immune response;
• The tumour burden should be small;
• BCG must come into direct contact with the tumour; and
• The dose must be adequate to stimulate an immune reaction.

The current evidence suggests that the use of an established BCG strain from another country does not disadvantage patients with bladder cancer. However, healthcare professionals are advised to take additional care when dispensing and administering any product that they are not familiar with.

Further information:

• OncoTICE – consult the Australian-approved product information;
• VesiCulture – consult the Instructions for Use; and
• Australia and New Zealand Urological Nurses Society publishes guidelines on Intra-vesical therapy for Non-Muscle Invasive Bladder Cancer (NMIBC).

Early recognition and prevention of patient deterioration is an important component of the healthcare system. The use of medical emergency teams (METs), also known as rapid response teams (RRTs), is recommended by the Australian Resuscitation Council to respond to instances of acute patient deterioration.

A small number of studies have demonstrated the benefits of pharmacist involvement in both MET and Code Blue teams. With up to a quarter of MET calls potentially caused by medicines, there is an obvious role for pharmacists as the majority of these could be potentially preventable.

Medicines affecting the cardiovascular system contributed to 60% of the total medication errors. Tachycardia due to omission of beta blockers, and hypotension due to cumulative toxicity or inappropriate use of antihypertensive during acute illness were the most common causes of potentially preventable medication-related MET calls.

A study conducted in the United States which reviewed surgical RRTs identified that 88% of calls were for impending respiratory failure due to excessive fluid administration in surgical patients.

Pharmacists can provide support by reviewing patients when they deteriorate and assist in identifying potential medicine causes. They can play an essential role by providing clinical advice on medication dosing, administration, and IV compatibility, and ensuring the MET team has the necessary medicines when they are required.

There are currently no standard recommendations for which medicines should be available for MET, and practice varies widely between hospitals. Principles to facilitate safe, timely and effective access to, selection of, and administration of medicines have been proposed. These include:

• MET medicine management should be multidisciplinary, involving ward staff and MET nurses, doctors and pharmacists.
• Medicines should be available to the MET to manage the common causes of MET activation, but not duplicate other resources.
• Changes to medicine supplies should be based on the best available evidence, including feedback from ward and MET clinicians, data from local MET calls, interventions, and activation triggers, in addition to published literature and guidelines.

Frequent causes of patient deterioration and MET activation include pulmonary oedema, sepsis, arrhythmias and seizures.

Basic life support (BLS) steps include early detection and timely intervention of patient deterioration to stop progress to cardiac arrest. All hospital staff should be able to recognise cardiac arrest, call for help, start cardiopulmonary resuscitation and defibrillate using an automated defibrillator. The purpose of BLS is to maintain myocardial and cerebral oxygenation until advanced life support (ALS) personnel and equipment are available.

Granulocyte colony-stimulating factor (G-CSF) is a blood growth factor naturally found in the body. G-CSF stimulates the survival, proliferation, differentiation and function of neutrophil granulocyte progenitor cells and mature neutrophils. Under stress, such as infection, high doses of chemotherapy and inflammation can stimulate G-CSF production, which in turn stimulates neutrophil production in the bone marrow and mobilises the neutrophils throughout the body.

Neutrophils are short-lived granulocytes produced in the bone marrow from common myeloid progenitor cells. Neutrophils compromise the majority of white blood cells. Neutrophils ingest, kill and digest pathogens. It helps the immune system fight infections and heal injuries.

A common side effect of chemotherapy is neutropenia, as chemotherapy targets rapidly dividing cells such as myeloblasts, which are the precursor to neutrophils. Since neutrophils are crucial to fighting infections, patients undergoing chemotherapy can be at risk of febrile neutropenia. Febrile neutropenia is a life-threatening condition where patients experience a fever greater than 38.3°C and an absolute neutrophil count of less than 0.5 x 10⁹ cells/L. Patients with febrile neutropenia are required to be hospitalised, and IV antibiotics are administered.

The discovery of G-CSF in the body and its isolation has led to the development of exogenous G-CSF, starting with filgrastim. G-CSF injections can be used to accelerate the proliferation and differentiation of progenitor cells. This rapidly results in more neutrophils available, which shortens the neutropenia phase. Recombinant G-CSF injections reduce the risk of febrile neutropenia by increasing neutrophil count. There are many indications for G-CSF, which include reducing the risk and duration of neutropenia after chemotherapy, mobilisation of stem cells for transplantation and severe chronic neutropenia.

There are three types of G-CSF injections currently readily available, which are pegfilgrastim, filgrastim and lipegfilgrastim.

Pegfilgrastim

Pegfilgrastim is given as a single dose of 6mg subcutaneously. Pegfilgrastim is a pegylated form of filgrastim, which has a longer half-life and lower renal clearance compared to filgrastim. Pegfilgrastim is given at least 24 hours after a chemotherapy cycle, and is usually only required once each chemotherapy cycle. It is usually given 1 to 3 days after completion of chemotherapy.  It is recommended to give chemotherapy only after 14 days from the last pegfilgrastim injection. There is a risk of severe thrombocytopenia if pegfilgrastim is given with concurrent chemotherapy. A common side effect patients experience is bone pain, which also indicates that the medication is working. Patients can take paracetamol to help with the pain. A rare adverse effect which can be fatal if not treated is splenic rupture, which presents as left upper abdominal pain or shoulder pain. Hence patients should be counselled about the difference in pain experienced. Compared to daily filgrastim injections, pegfilgrastim is more convenient to use for patients.

Filgrastim

Compared to the other two, filgrastim is given as a daily injection. Unlike the other two, filgrastim is non pegylated. It can be given as a subcutaneous or intravenous injection. The usual dose is 5-10mcg/kg and rounded up to the nearest vial or syringe size for adults which is given over several days. Chemotherapy is safe to give 24 hours after filgrastim injections. Per eviQ guidelines, filgrastim is used for peripheral blood stem cell mobilisation for use in allogeneic peripheral blood progenitor cell transplantation.

Lipegfilgrastim

Lipegfilgrastim is also given as a single dose of 6mg via subcutaneous injection 24 hours after chemotherapy. It is also a pegylated form of filgrastim and is long acting. Lipegfilgrastim has a longer half-life compared to pegfilgrastim. It has been shown to induce a longer lasting increase in neutrophil counts and a greater time-dependent resistance to neutrophil elastase degradation compared to pegfilgrastim. However, from studies, it is shown to be non-inferior to pegfilgrastim. The side effects are also similar to the others, with bone pain being the most common side effect.

Urinary incontinence refers to the involuntary leakage of urine. The condition is common in the elderly but can also affect younger adults. While urinary incontinence is thought to affect up to 10% of men and 38% of women in Australia, it is likely underdiagnosed and undertreated. Patients may be hesitant to report symptoms for a variety of reasons, such as embarrassment, a belief that incontinence is a normal part of ageing, or a lack of awareness of treatment options.

Urinary incontinence can be divided into categories based on the underlying cause. The most common types are:

• Stress urinary incontinence – related to weakness of the urethral sphincter and/or the pelvic floor. This results in the leakage of urine when intra-abdominal pressure increases, as can occur during sneezing, coughing, or physical exertion;
• Urge urinary incontinence – related to detrusor overactivity, which may be due to bladder irritation or loss of neurologic control;
• Mixed urinary incontinence – a combination of stress and urge incontinence;
• Overflow urinary incontinence – bladder outlet obstruction or impaired detrusor contractility can cause overdistension of the bladder, resulting in leakage. Benign prostatic hyperplasia (BPH) is a common cause of this in men. Other potential causes include spinal cord injuries, multiple sclerosis, diabetes, or external compression from pelvic organ prolapse or abdominal or pelvic masses;
• Functional urinary incontinence – the urinary system is functioning correctly, but another illness or disability is causing incontinence. For example, dementia or sedative medications can reduce the awareness of needing to go to the toilet. Alternatively, some disabilities can make it difficult for a person to get to the toilet and undress in time. Treatment of functional urinary incontinence typically focuses on improving functional status, reducing environmental barriers to toileting, and treating any modifiable causes of incontinence.

It is important that the cause of the incontinence is investigated as management differs depending upon the type of incontinence. Treatment may be conservative (e.g. behavioural therapies, pelvic floor exercises, weight loss), surgical, pharmacological, or a combination of modalities.

Anticholinergics and mirabegron are the main drugs used in the treatment of urinary urge incontinence. Botulinum toxin type A can be considered for certain patients who do not respond or do not tolerate anticholinergics. However, this is a more invasive option.

Anticholinergics

Anticholinergics are mainly used in the management of urinary urge incontinence. They work by reducing bladder muscle contractility and increasing bladder storage capacity. However, they can increase voiding dysfunction, causing urinary hesitancy and retention in some cases.

Medications in this class include:

• Darifenacin;
• Oxybutynin;
• Propantheline (rarely used);
• Solifenacin; and
• Tolterodine.

There are five subtypes of muscarinic receptors, with bladder contraction being primarily controlled by the M3 subtype. Oxybutynin, propantheline, and tolterodine are non-selective in that they exert effects in the bladder, as well as the gut and salivary glands. However, tolterodine has greater specificity for the bladder when compared to oxybutynin and may cause less dry mouth. Solifenacin and darifenacin are considered M3-selective agents and act mainly on the bladder. Selective agents may have a more favourable adverse effect profile, but can still be associated with anticholinergic adverse effects outside of the bladder.

The effectiveness of anticholinergics varies considerably between individuals. One review suggests that these medications are associated with an average of one fewer episode of incontinence per 48 hours compared to placebo. While this may not seem impressive, many of the studies included in this review did not utilise optimal clinical practice (i.e. concomitant bladder training) and most did not measure the effect on urinary urgency or quality of life.

Adverse effects

Adverse effects are typically dose-related but also depend upon patient factors, such as age and comorbidities. Particular caution is required in the elderly as they are more sensitive to the effects of anticholinergics and are more likely to be already taking medication with anticholinergic properties. The overall anticholinergic burden should be considered when using these medications in the elderly.

Anticholinergic adverse effects include urinary retention, dry mouth, constipation, dyspepsia, blurred vision, dry eyes, tachycardia, arrhythmia, dizziness, drowsiness, headache, hallucinations, confusion, and memory impairment. Oxybutynin is commonly associated with central effects, while these are unlikely with propantheline as it does not readily cross the blood-brain barrier. Dry mouth is also more likely with oral oxybutynin. Solifenacin may increase the QT interval, particularly in patients with known risk factors (e.g. history of QT prolongation, hypokalaemia).

Mirabegron

Mirabegron is used to treat urinary urgency, frequency, and incontinence in patients with overactive bladder (OAB) syndrome.

Mirabegron is an agonist at the beta₃-adrenoceptor. Studies demonstrate that relaxation of human bladder smooth muscle is largely mediated by the beta₃-adrenoceptor. Mirabegron relaxes the bladder, increases the amount of urine it can hold, and also improves bladder emptying.

Adverse effects

Mirabegron is generally well tolerated which is likely due to the limited expression of beta₃-adrenoceptors in other parts of the body. Mirabegron has very low intrinsic activity for beta₁ and beta₂-adrenoceptors which translates into little effect on the cardiovascular system. However, some beta₁ stimulation occurs with doses above 50mg. This may cause increased blood pressure and heart rate. Blood pressure should be monitored during treatment, and mirabegron should not be initiated in patients with severe uncontrolled hypertension.

Botulinum toxin type A

Botulinum toxins may be used in the management of urinary incontinence related to neurological illness (e.g. multiple sclerosis or spinal cord injury) or OAB. Botulinum toxin can be administered by intradetrusor injection. This therapy reduces detrusor contractility by blocking the release of acetylcholine into the neuromuscular junction.

Clinical improvement may occur within two weeks of administration. Re-dosing may be considered when the effects have diminished, but there should be at least three months between doses. In clinical studies, the median duration between injections for OAB was around six months.

Adverse effects

Adverse effects include urinary tract infection (UTI), urinary retention, dysuria, and haematuria. The patient must not have a UTI at the time of administration. The manufacturer recommends prophylactic antibiotics to be given one to three days before treatment, on the day of treatment, and for up to three days after treatment.

There is a lack of data regarding the intradetrusor injection of botulinum toxin in patients taking antiplatelet or anticoagulant medications. These patients were either excluded from initial trials or ceased their anticoagulant or antiplatelet a week prior to the procedure. A recently published retrospective review suggests that continuing anticoagulants and antiplatelet medicines may be safe during therapy with intradetrusor botulinum toxin. However, the manufacturer recommends that antiplatelet therapy be discontinued at least three days before injection.

Selective alpha antagonists

Selective alpha antagonists may be used to manage urge incontinence, overflow incontinence, and other symptoms associated with BPH. These medications block alpha₁ receptors, relaxing the muscles of the prostate and urethra. This results in increased urinary flow rate and reduced obstruction.

Medications in this class are:

• Alfuzosin;
• Prazosin;
• Silodosin; and
• Tamsulosin.

These medications can improve urinary symptoms within 48 hours, with the full effect seen in four to six weeks. The efficacy of selective alpha antagonists does not appear to be dependent upon the prostate size.

Common adverse effects include first-dose hypotension, orthostatic hypotension, and dizziness. These are all more common with prazosin and may be minimised by starting with a low dose. Other common adverse effects with this medication class are nasal congestion, urinary urgency, headache, weakness, and fatigue.

5-alpha reductase inhibitors

These medications inhibit 5-alpha reductase, an enzyme responsible for converting testosterone to dihydrotestosterone (a potent stimulant of prostate growth). Inhibition of this enzyme can alleviate lower urinary tract symptoms associated with BPH. It may take six months or more to notice an improvement in symptoms following the initiation of a 5-alpha reductase inhibitor. Efficacy is dependent on prostate size, and men with larger prostates are likely to respond better.

Examples include dutasteride and finasteride. Dutasteride is also available in a fixed-dose combination with the selective alpha-blocker, tamsulosin.

Common adverse effects of this class include fatigue, loss of libido, erectile dysfunction, and ejaculation disorder.

Estrogens

Topical estrogen can be used in perimenopausal or postmenopausal women with urge incontinence and vaginal atrophy due to genitourinary syndrome of menopause (GSM). Options include creams and pessaries.

Systemic estrogen is not recommended for urinary incontinence, as the evidence suggests that this may worsen the issue.

Tricyclic antidepressants

Tricyclic antidepressants reduce bladder contractility and increase urethral resistance. Amitriptyline and imipramine are approved for the treatment of nocturnal enuresis.

The side effect profile of this class limits their usefulness for the treatment of incontinence. Common side effects include sedation, dry mouth, orthostatic hypotension, and confusion. They can also affect cardiac conduction and are rarely associated with hepatitis and blood dyscrasias.

Drugs contributing to incontinence

There are many medications that have been implicated in causing or exacerbating urinary incontinence, including:

• ACE inhibitors and angiotensin receptor blockers – blocking the renin-angiotensin system reduces detrusor overactivity and urethral sphincter tone. Therefore, these medications can worsen stress incontinence but may improve urge incontinence;
• Alpha-antagonists – while these agents may be used to treat urinary symptoms related to BPH, they can cause incontinence due to reduced bladder outlet resistance;
• Anticholinergics – while these medicines are often used to treat urge incontinence, they can indirectly cause overflow incontinence due to urinary retention;
• Antipsychotics – many antipsychotics are associated with urinary incontinence, including chlorpromazine, thioridazine, trifluoperazine, and haloperidol;
• Calcium channel blockers – inhibit bladder contractions and may cause overflow incontinence due to urinary retention;
• Diuretics – may cause frequency, urgency and incontinence due to increased urine production. This is particularly evident with loop diuretics such as furosemide; and
• Sedative-hypnotics – can contribute to functional incontinence.

Summary

Drug treatment for urinary incontinence typically has only modest benefits and may be limited by adverse effects. Anticholinergics are commonly used, although mirabegron is a newer option that may be better tolerated.

A summary of commonly used medications is shown in Table 1.

Table 1. Overview of medications for urinary incontinence

Medication	Condition treated	Usual dosing frequency	PBS listed for incontinence
Anticholinergics
Darifenacin	Urge incontinence	Daily	No
Oxybutynin		2-3 times daily (oral) Twice weekly (patch)	Yes
Propantheline		2-3 times daily	Yes
Solifenacin		Daily	No
Tolterodine		Twice daily	No
β3-agonist
Mirabegron	Overactive bladder	Daily	No
Botulinum toxins
Botulinum toxin type A	Overactive bladder	~6 monthly	Yes
Selective alpha antagonists
Alfuzosin	Lower urinary tract symptoms of BPH	Daily	Yes (repat)
Prazosin		Twice daily	Yes
Silodosin		Daily	Yes (repat)
Tamsulosin		Daily	Yes (repat)
5-alpha reductase inhibitors
Dutasteride	Lower urinary tract symptoms of BPH	Daily	Yes
Finasteride		Daily	Yes (repat)
Topical estrogens
Estriol	Stress or urge incontinence due to GSM	1-2 times weekly	Yes
Estradiol		Weekly	Yes
Tricyclic antidepressant
Amitriptyline	Nocturnal enuresis Stress/mixed incontinence	Daily	Yes
Imipramine		Daily	Yes

Prostate cancer is one of the most commonly diagnosed cancers in Australia, where it is estimated that 1 in 6 males will be diagnosed with prostate cancer by the age of 85. Prostate cancer starts from abnormal cells growing uncontrollably in the prostate gland, which can result in a malignant tumour. Prostate cancer cell growth is stimulated by androgens, which are mainly testosterone and dihydrotestosterone. Hence, reducing androgen levels is the main goal in treating prostate cancer. Prostate cancer is managed with a variety of treatments, including surgery, chemotherapy, radiation and androgen-deprivation therapies. However, over time, many patients acquire castration resistance, where the cancer no longer completely responds to testosterone-lowering treatment. The adrenal glands and prostate cancer tissue continue to produce androgens, which contribute to prostate cancer growth. This results in castrate-resistant prostate cancer, which is difficult to treat and associated with poor prognosis.

It is found that castration-resistant prostate cancer is often associated with increased PSA (prostate-specific antigen) levels, which suggests that prostate cancer continues to be driven by androgen-receptor signalling despite androgen-deprivation therapy. Androgen receptor mutations, adrenal gland testosterone production and intratumoral androgen production, are some of the reasons prostate cancer progresses. Hence, it suggests that further suppression of androgen-receptor signalling may give options to treat castrate-resistant prostate cancer.

Over the last ten years, there have been many advances in endocrine therapies which have improved survival in patients with castrate-resistant prostate cancer. Various novel oral anti-androgen therapies have been included under the Pharmaceutical Benefits Scheme to treat castrate-resistant prostate cancer. This includes darolutamide, apalutamide, abiraterone and enzalutamide. Darolutamide, apalutamide and enzalutamide belong to the same class of second-generation antiandrogens. Abiraterone works differently by blocking cytochrome P450 17 alpha-hydroxylase (CYP17) to reduce androgen production.

Darolutamide, enzalutamide and apalutamide are second-generation antiandrogens, where first-generation antiandrogens include bicalutamide. Compared to bicalutamide, it is found that the second-generation anti-androgens tend to have a much higher affinity for the androgen receptor, where apalutamide has a 7 to 10-fold increased affinity and enzalutamide a 5 to 8-fold increased affinity compared to bicalutamide. All anti-androgens can cause infertility in males.

Darolutamide (Nubeqa®)

The usual dose of daroluatmide is 600mg twice a day. Due to the low bioavailability of darolutamide, it needs to be taken with food. Darolutamide needs to be dose reduced to 300mg twice daily in patients with reduced kidney function (15 to 30 mL/min/1.73m²) and those with moderate hepatic impairment. Darolutamide is a mild CYP3A4 substrate. Caution should still be warranted when a patient is on an existing drug which is either a strong inhibitor or inducer of CYP3A4 as this can affect the levels of darolutamide. However, compared to apalutamide and enzalutamide, it is least affected by CYP metabolism, which results in less drug interactions. The most common adverse effect of darolutamide is fatigue. If the fatigue is severe, treatment is delayed until resolved or the dose reduced to 300mg twice daily.

Enzalutamide (Xtandi®)

Enzalutamide comes as 40mg capsules. The usual dose is 160mg once daily and can be taken with or without food. Depending on symptoms, the dose can be reduced. It does not need dose adjustment in patients with hepatic impairment or creatinine clearance greater than 30 mL/min/1.73.m². It has not been studied in patients with creatinine clearance lower than 30. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. This means that the co-administration of enzalutamide with drugs with a narrow therapeutic index that are substrates of CYP3A4, CYP2C9 or CYP2C19 is not recommended. These include commonly seen drugs such as warfarin (CYP2C9) and colchicine (CYP3A4). The common adverse effects of enzalutamide include fatigue, muscle pain, fractures and hypertension. Fatigue is the most common side effect however it can be accumulative and severe. A dose reduction to 120mg daily is recommended on first occurrence, however if it is ongoing, it is suggested to switch to a different therapy.

Apalutamide (Erlyand®)

Apalutamide is readily absorbed and can be taken with or without food. It comes as 60mg tablets and the usual dose is 240mg daily. No dose adjustments are recommended in hepatic and renal impairment, however it has not been studied in patients with severe hepatic impairment or patients with eGFR less than 30 mL/min/1.73m². Apalutamide is a substrate of CYP3A4/5 and CYP2C8. It is a weak inducer of CYP2C9 but a strong inducer of CYP2C19 and CYP3A4/5. Common side effects include fatigue, hypertension, rash, falls and fractures. From trials studying apalutamide, it is found that ischaemic cardiovascular events have been associated with apalutamide which have resulted in death. It is important to monitor for signs and symptoms of ischaemic heart disease and reduce the dose of apalutamide or cease.

Abiraterone (Zytiga®)

Abiraterone comes as 250mg or 500mg tablets. The dose is 1g once daily. It is taken on an empty stomach, at least two hours after food and wait at least one hour before eating again. Taking abiraterone with food can increase the risk of side effects. Unlike the other second-generation antiandrogens, abiraterone is taken together with prednisone/prednisolone 10mg daily. This is due to the mechanism of action of abiraterone, where it not only suppresses testosterone but also cortisol production. This results in lower cortisol levels and a compensatory increase in adrenocorticotropic hormone (ACTH). Prednisone acts as a glucocorticoid replacement therapy to reduce mineralocorticoid-related adverse effects such as fluid retention, hypertension and hypokalaemia. Due to these common side effects, patients on abiraterone need to monitor for blood pressure, potassium concentration, fluid retention as well as liver function. Abiraterone is mainly eliminated via the liver so it is contraindicated in severe hepatic impairment.

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