Knowledge Type: Clinical Articles

Clostridium difficile is the most common cause of infectious diarrhoea in hospitalised patients. This anaerobic, spore-forming bacteria is prevalent in the environment and can be spread directly or indirectly via the faecal-oral route. C. difficile presents a challenge as the spores can survive in the environment for long periods and are resistant to many disinfectants.

Asymptomatic colonisation with C. difficile is common, particularly amongst hospitalised patients, nursing home residents, and infants. Symptomatic infection may then occur following a disruption of the host’s microbiome that favours C. difficile germination and growth. Antibiotic use is the most common cause of this disruption. While all antibiotics are thought to be capable of causing C. difficile infection (CDI), broad-spectrum antibiotics such as cephalosporins, quinolones, and lincosamides are associated with the highest risk. Other risk factors include hospitalisation, cancer chemotherapy, advanced age, and the use of proton pump inhibitors.

The C. difficile bacterium produces two exotoxins, toxin A and toxin B. Some strains also produce another toxin called binary toxin. Although binary toxin is sometimes associated with increased disease severity, its role is poorly understood. Toxins A and B damage the lining of the colon which can result in symptoms such as fever, watery diarrhoea, and abdominal pain. In more severe cases, the diarrhoea may be particularly frequent and lead to severe dehydration. Blood or pus may also be visible in the stools.

The Therapeutic Guidelines provide the following recommendations for the treatment of CDI.

• First episode:
  • Metronidazole (orally or enterally), or
  • Vancomycin (orally or enterally)
• First recurrence:
  • Vancomycin (orally or enterally), or
  • Fidaxomicin orally
• Second and subsequent recurrences or ongoing refractory disease (adults):
  • Faecal microbiota transfer (if available),
  • Vancomycin (orally or enterally), or
  • Fidaxomicin orally
• Second and subsequent recurrences or ongoing refractory disease (children):
  • Vancomycin (orally or enterally), or
  • Nitazoxanide orally.

All patients with severe disease require specialist review. The rate of severe CDI has been increasing in recent years and accounted for 2.2% of all CDI cases seen in Australian hospitals in 2015. Signs and symptoms of severe disease include leucocytosis, severe abdominal pain, elevated serum creatinine, elevated blood lactate, low serum albumin, high fever, or organ dysfunction. Outbreaks of hypervirulent strains have been reported in Australia since 2000.

A diagnosis of CDI continues to be associated with considerably longer hospital stays. The average length of stay for all CDI cases is reported to be 17.7 days, although there are marked differences for patients presenting with CDI as the principal diagnosis (7.9 days) compared to CDI as an additional diagnosis (21.6 days). This represents a significant increase in healthcare costs in addition to the increased morbidity and mortality associated with infection. Around 20% of patients with an initial infection will experience at least one other episode. Recurrent CDI is often more difficult to treat and associated with worse outcomes and higher costs than initial infections. Therefore, interventions that prevent recurrence are of great interest.

Bezlotoxumab is a new medication available for the prevention of C. difficile recurrence in adults who are at high risk. Bezlotoxumab is a monoclonal antibody that binds to toxin B with high affinity, neutralising its activity. Clinical trials demonstrate a sustained cure rate of 64% in patients treated with bezlotoxumab plus standard of care antibacterial therapy compared to 54% for standard of care therapy alone. The rate of adverse events was similar amongst the two groups; infusion-related reactions occurred in 10.3% of patients receiving bezlotoxumab (7.6% placebo). The other most commonly reported adverse events in each group include abdominal pain, diarrhoea, and nausea. Bezlotoxumab has a terminal half-life of around 19 days. This allows the use of a single infusion during a course of antibiotic treatment. As bezlotoxumab is not an antibacterial agent, it must be co-administered with appropriate antibacterial therapy.

Bezlotoxumab is not active against toxin A. However, it is thought that toxin B is the main determinant of virulence in recurrent CDI. Clinical studies of actoxumab, an experimental antibody against toxin A, support this idea. Actoxumab has not demonstrated efficacy when used as a single agent and does not improve efficacy when added to bezlotoxumab.

The role of bezlotoxumab in the management of C. difficile infection is currently uncertain. Further studies are required to determine the optimal timing of infusion and the patients most likely to benefit from this preventative therapy.

Asthma is a chronic lung disease affecting one in nine Australians. The condition is characterised by hypersensitivity and inflammation of the airways which results in symptoms such as cough, wheeze, chest tightness, and breathlessness. While many people with asthma lead fit and healthy lives, the condition was responsible for 421 deaths and 39,448 hospitalisations in Australia in 2015. This highlights the need for optimisation of management strategies.

The National Asthma Council Australia (NACA) recently published an updated version of the Australian Asthma Handbook. The handbook is designed to provide healthcare professionals with best-practice, evidence-based advice for the management of asthma. The following revisions found in version 2.0 of the handbook are supported by current clinical evidence.

Recommendations for infants and children

• Infants younger than 12 months of age should not be treated for acute asthma as acute wheeze in this age group is most likely due to viral bronchiolitis. Other possible alternative diagnoses include tracheobronchomalacia, airway lesion, cardiac left-to-right shunt, and an inhaled foreign body (if wheeze is unilateral). It is recommended to seek the advice of a paediatrician or paediatric respiratory physician before β₂ agonists or corticosteroids (inhaled or systemic) are administered to an infant;
• Loading doses are no longer recommended for systemic corticosteroids in children. This change has occurred as the loading doses typically used are not well supported by the current evidence. Avoidance of these higher initial doses is advised in order to reduce systemic corticosteroid exposure; and
• Paediatric use of antibiotics, proton pump inhibitors and antacids should be restricted to cases where a clinical benefit is likely. Current evidence suggests a possible association between the use of these medications (particularly during the first six months of infancy) and an increased risk of developing asthma and allergic diseases. A large retrospective study demonstrates a greater than two-fold risk of developing asthma in childhood when antibiotics are prescribed in the first six months of life. The adjusted hazard ratios for acid-suppressing medications was somewhat lower at 1.25 for H₂ antagonists and 1.41 for proton pump inhibitors.

Recommendations during pregnancy

• The latest version of the handbook stresses that the unnecessary use of antibiotics during pregnancy must be avoided. Emerging evidence suggests that the maternal microbiome may influence the development of the foetal immune system and possibly play a role in the prevention of allergy-prone phenotypes. Research is continuing in this area to explore possible confounders such as the timing of antibiotic therapy, the spectrum of antibiotic used, and the indication for antibiotic treatment; and
• Women who are pregnant or planning to become pregnant should follow current national guidelines for vitamin D supplementation. Available evidence suggests that adequate vitamin D during pregnancy may reduce the risk of asthma and recurrent wheeze in the offspring.

Changes in the management of exacerbations

• Oral dexamethasone has been added as an alternative to oral prednisolone. Current clinical evidence demonstrates that oral dexamethasone is as effective as prednisolone in adults and children for the treatment of acute asthma. Dexamethasone is a potent corticosteroid with a glucocorticoid activity around six times greater than prednisolone. However, dexamethasone displays only negligible mineralocorticoid activity which translates to fewer adverse effects related to sodium retention. The half-life of dexamethasone is considerably longer than prednisolone (36-72 hours compared to 12-36 hours) which may improve compliance as shorter courses are required. Oral dexamethasone treatment is not recommended to exceed two days duration;
• Ipratropium has been added to the routine treatment of children and adults with severe or life-threatening acute asthma. Clinical studies demonstrate that the use of ipratropium with an inhaled short-acting β₂ agonist reduces hospitalisation in adults with severe acute asthma and children with moderate to severe acute asthma compared to a β₂ agonist alone. While this combination is often well tolerated, it may be associated with a higher incidence of adverse effects such as tremor, agitation, and palpitations;
• Risk factors for poor outcomes have been added to the criteria for hospital admission in addition to the patient’s clinical status after treatment. This includes factors such as a history of ICU admission for asthma, presentation for acute asthma within the past four weeks, and recent high use of β₂ agonists. This revision aims to encourage a more comprehensive assessment of risk and reduce the risk of life-threatening relapse shortly after discharge from hospital; and
• Expansion of recommendations to prescribe inhaled corticosteroids at discharge to reduce the risk of future acute exacerbations. If an inhaled corticosteroid has already been prescribed, hospital admission is an opportune time to check adherence and inhaler technique. Regular inhaled corticosteroid therapy is indicated for adults and adolescents over 12 years of age who have had an asthma exacerbation in the previous 12 months and for those whose asthma is not well controlled (i.e. asthma symptoms twice or more during the previous month or waking due to symptoms once or more during the past month).

Optimal therapy including regular preventative medications (where indicated), timely and appropriate treatment of exacerbations, and management of modifiable risk factors can reduce the morbidity and mortality associated with this chronic disease. For a comprehensive review of all recent updates, please refer to the Australian Asthma Handbook.

There are currently five heparins registered for use in Australia: dalteparin, danaparoid, enoxaparin, heparin, and nadroparin. Table 1 highlights some of the important differences between these parenteral anticoagulants.

Table 1. A comparison of heparin medications

Drug	Selected indications	Onset	Usual dosing interval	Monitoring	Antidote
Heparin
Heparin	VTE prophylaxis; Therapeutic anticoagulation	IV: immediate SC: variable (20-60 mins)	8-12 hourly/ continuous IV infusion	Dose adjusted according to aPTT	Protamine (complete reversibility)
Low molecular weight heparins
Dalteparin	VTE prophylaxis; Therapeutic anticoagulation	Within 3 hours	Daily	Antifactor Xa may be monitored in patients at high risk of bleeding	Protamine (partial reversibility)
Enoxaparin			Daily/twice daily
Nadroparin			Daily
Heparinoid
Danaparoid	Surgical VTE prophylaxis	Peak activity: 4-5 hours	Twice daily	Dose adjusted according to antifactor Xa level	No antidote

Abbreviations: VTE, venous thromboembolism; IV, intravenous; aPTT, activated partial thromboplastin time.

Heparin

Heparin, also known as unfractionated heparin, is a naturally occurring mucopolysaccharide. Its anticoagulant effect is achieved by potentiation of antithrombin III which enhances the inactivation of thrombin and factor Xa. However, this effect is thought to be somewhat dose-dependent. Anticoagulation from low-dose heparin therapy appears to occur primarily through neutralisation of factor Xa with a consequent reduction in conversion of prothrombin to thrombin. High-dose heparin therapy achieves anticoagulation from neutralisation of thrombin, thereby inhibiting the conversion of fibrinogen to fibrin. High doses also inhibit the activation of fibrin stabilising factor, further preventing the formation of a stable fibrin clot.

Heparin is one of the oldest medications still in common use today. However, it does have a number of limitations, including:

• Wide variability in anticoagulant response. This is partly due to the heterogeneity of heparin which is a mixture of polysaccharides with varying molecular weights.
• Complex clearance that is significantly affected by dose. Low doses may be removed by a rapid, but quickly saturable mechanism. Subsequent clearance occurs via slower non-saturable pathways that are heavily reliant on renal mechanisms. Therefore, the relationship between dose and steady-state concentration is non-linear during continuous IV infusion;
• Careful monitoring is required when administered by IV infusion (anticoagulant effect and platelet count);
• The relatively short half-life (around 30 minutes following IV injection) necessitates multiple daily doses or administration of a continuous infusion. However, this shorter duration of action may be beneficial in the perioperative setting where the risk of bleeding is high; and
• Risk of heparin-induced thrombocytopenia (HIT). HIT is a life and limb-threatening immune complication of heparin therapy. Occurring in around 2.6% of surgical patients, HIT is often considered heparin’s most clinically significant non-haemorrhagic adverse event.

Low molecular weight heparins

Low molecular weight heparins (LMWH) are a group of chemically distinct compounds produced via depolymerisation of unfractionated heparin. This results in shorter fragments and a lower mean molecular weight. Like heparin, LMWHs also potentiate the action of antithrombin III. However, due to their reduced size, LMWHs have a greater effect on factor Xa than on thrombin.

LMWHs offer many advantages, including:

• Greater bioavailability (around 90% compared to 30-40% for unfractionated heparin);
• Longer half-lives. This enables daily (or twice daily) dosing;
• A more predictable anticoagulant response. This allows fixed-dose administration without the need for routine laboratory monitoring; and
• A lower risk of HIT (0.2% compared to 2.6% for heparin in surgical patients). However, LMWHs are not recommended to be used in patients with a history of HIT as cross-reactivity can occur.

LMWHs are almost exclusively cleared by the renal system. While this offers more predictable clearance independent of dose, accumulation can occur in renal insufficiency. Therefore, dosage reduction and monitoring may be required for patients with renal impairment. Heparin remains the preferred option in patients with severe renal impairment.

Danaparoid

Danaparoid is a low molecular weight heparinoid that is approved for VTE prophylaxis in surgical patients. Like the LMWHs, danaparoid is largely renally cleared and should be avoided in patients with severe renal impairment. Unlike LMWHs, danaparoid has a much lower cross-reactivity in producing thrombocytopenia in patients with a history of HIT. Consequently, danaparoid may be used under specialist direction to treat thromboembolic disease in patients with HIT or a history of HIT.

Conclusion

While these medications share many similarities, they cannot be considered interchangeable. It is also important to remember that anticoagulants are regarded as high-risk medications. Great care should be taken when handling heparins to avoid medication errors. Many of these medications are available in a range of strengths. For example, heparin is formulated as a 50 IU/5mL injection (heparinised saline) that is used to maintain the patency of intravenous injection devices. However, heparin is also available for therapeutic and prophylactic use in various strengths up to 25,000 IU/5mL. Careful attention to strength and dose is required as errors with these products have a high risk of serious patient harm.

It is estimated that 45% of Australians will experience a mental health issue in their lifetime, with around 20% reporting experience of a mental health issue over any 12 month period. These figures clearly demonstrate the significance of mental health in the health care setting. However, it is well documented that people with serious mental illness access physical health services less, and receive less care when they do access services. This leads to poorer health outcomes and contributes to the significant gap in life expectancy between people with mental health issues and those without.

The Royal Australian and New Zealand College of Psychiatrists report that the life expectancy for adults with serious mental illness is up to 30% shorter than the general population. Around 80% of the excess deaths in people with serious mental illness are due to physical health conditions, rather than the mental illness. One large retrospective analysis demonstrated that the most common causes of death in people with mental illness were also common causes of death in the general population (i.e. cardiovascular disease, respiratory disease, and cancer).

The Australian Commission on Safety and Quality in Health Care (the Commission) developed the National Safety and Quality Health Service (NSQHS) Standards to provide a nationally consistent description of the standard of care that should be expected in an Australian healthcare facility. The second edition of the NSQHS Standards, released in 2017, contains the following eight standards:

1. Clinical governance;
2. Partnering with consumers;
3. Preventing and controlling healthcare-associated infection;
4. Medication safety;
5. Comprehensive care;
6. Communicating for safety;
7. Blood management; and
8. Recognising and responding to acute deterioration.

While these standards are applicable to all Australian healthcare facilities, the Commission has identified a number of actions that will be particularly useful to improve the delivery of healthcare to people with mental health issues. These actions, shown in Table 1, are highlighted in the recently published NSQHS Standards User Guide for Health Services Providing Care for People with Mental Health Issues. While this guide contains information that may be useful to specialist mental health services, it is also intended for healthcare facilities that do not specialise in mental health services to support the provision of care to people with existing or emerging mental health issues.

Table 1. NSQHS Standards of particular importance to mental health

Standard	Criterion	Item	Actions
1. Clinical governance	Governance, leadership and culture	Governance, leadership and culture	1.1
		Organisational leadership	1.3
		Clinical leadership	1.6
	Patient safety and quality systems	Policies and procedures	1.7
		Measurement and quality improvement	1.9
		Risk management	1.10
		Incident management systems and open disclosure	1.11
		Feedback and complaints management	1.13, 1.14
		Diversity and high-risk groups	1.15
	Safe environment for the delivery of care	Safe environment	1.29, 1.30
2. Partnering with consumers	Partnering with patients in their own care	Healthcare rights and informed consent	2.4, 2.5
		Sharing decisions and planning care	2.6, 2.7
4. Medication safety	Documentation of patient information	Medication reconciliation	4.5, 4.6
		Adverse drug reactions	4.7
5. Comprehensive care	Developing the comprehensive care plan	Screening of risk	5.10
		Clinical assessment	5.11
		Developing the comprehensive care plan	5.13
	Delivering comprehensive care	Using the comprehensive care plan	5.14
	Minimising patient harm	Predicting, preventing and managing self-harm and suicide	5.31, 5.32
		Predicting, preventing and managing aggression and violence	5.33, 5.34
		Minimising restrictive practices: restraint	5.35
		Minimising restrictive practices: seclusion	5.36
6. Communicating for safety	Communication at clinical handover	Clinical handover	6.8
	Communication of critical information	Communicating critical information	6.9, 6.10
8. Recognising and responding to acute deterioration	Detecting and recognising acute deterioration, and escalating care	Recognising acute deterioration	8.5
		Escalating care	8.6
	Responding to acute deterioration	Responding to deterioration	8.12

The user guide provides detailed discussion, suggestions and examples on how health service organisations can integrate the above actions into their usual practice. For example, Standard 4 (Medication Safety) highlights the importance of taking a best possible medication history (BPMH). While this is important for all patients, studies have identified variance for the reconciliation of medications for physical and mental health conditions. Interruption to the provision of a patient’s regular medications may result in a deterioration of the original condition being treated and withdrawal symptoms. In the case of mental health, this may impact a patient’s decision making ability and result in poorer mental and physical health outcomes. It is recommended that a structured BPMH is taken by appropriately trained clinicians in a manner that does not stigmatise mental health issues or unintentionally discourage patients from revealing their existing treatment.

The overarching principles of the NSQHS Standards are that caring for a person’s mental and physical health must be an integrated process. It is now mandatory for health services assessed under the NSQHS Standards to address the actions detailed in the second edition of the standards. For services also using the National Standards for Mental Health Services (NSMHS), the Commission produces a map to demonstrate the alignment of the two standards.

The American Geriatrics Society (AGS) has recently updated the Beers Criteria for potentially inappropriate medication (PIM) use in older adults. The Beers Criteria is an evidenced-based approach to identify medications that are typically best avoided in people over 65 years of age. Medications included in this criteria are associated with poor health outcomes, including confusion, falls, and mortality. Therefore, avoiding PIMs in older adults could be expected to improve care by reducing exposure to medications with an unfavourable risk to benefit ratio.

The 2019 update is the result of an extensive systematic review and grading of evidence pertaining to drug-related problems and adverse events in older adults. Several medications have been removed from the criteria for the following reasons:

• The risks associated with the drug in question were not unique to older people (e.g. the use of stimulants in people with insomnia);
• The weak nature of evidence used to support the inclusion of the drug (e.g. H₂-receptor antagonists in dementia);
• The highly specialised nature of the drug made its use fall outside the scope of the criteria (e.g. chemotherapeutic agents such as carboplatin and vincristine); and
• The drug is no longer available.

A selection of medications included in the 2019 Beers Criteria of PIMs to avoid in older adults is shown in Table 1. The complete list can be found here.

Table 1. Potentially inappropriate medications to avoid in older adults.

Medication Class	Rationale	Recommendation
Anticholinergics Brompheniramine Chlorpheniramine Cyproheptadine Dexchlorpheniramine Dimenhydrinate Diphenhydramine Doxylamine Promethazine Triprolidine	Risk of anticholinergic adverse effects or toxicity. Clearance reduced with advanced age, tolerance develops to use as hypnotic.	Avoid Diphenhydramine may be appropriate in some situations (e.g. acute allergy).
Antiparkinsonian agents Benzatropine (oral) Trihexyphenidyl (benzhexol)	More effective agents available for the treatment of Parkinson’s disease (e.g. levodopa). Not recommended for treatment or prevention of extrapyramidal symptoms.	Avoid
Antispasmodics Atropine (excludes ophthalmic) Hyoscyamine Propantheline	Highly anticholinergic. Poor evidence to support efficacy.	Avoid
Nitrofurantoin	Potential for pulmonary toxicity, hepatotoxicity, and peripheral neuropathy. Safer alternatives available.	Avoid if CrCl <30mL/min. Avoid long-term use.
Prazosin (for hypertension)	High risk of orthostatic hypotension. Alternative agents have better risk/benefit profile.	Avoid use as an antihypertensive.
Central α-agonists Clonidine (for hypertension) Methyldopa	High risk of CNS effects. May cause bradycardia and orthostatic hypotension.	Avoid as first-line therapy for hypertension.
Disopyramide	Strongly anticholinergic Potent negative inotrope (may induce heart failure).	Avoid
Antidepressants Amitriptyline Clomipramine Desipramine Doxepin Imipramine Nortriptyline Paroxetine	Strongly anticholinergic Sedating May cause orthostatic hypotension.	Avoid
Antipsychotics	Increased risk of stroke, cognitive decline, and mortality in people with dementia. Avoid in dementia unless other options have failed and the patient is a significant threat to self or others.	Avoid (except in schizophrenia, bipolar disorder, or for short-term antiemetic use during chemotherapy).
Benzodiazepines	Increased risk of cognitive impairment, delirium, and falls. Older adults have greater sensitivity to these agents and reduced metabolism of long-acting agents (e.g. diazepam).	Avoid (may be appropriate for some indications such as seizure disorders and peri-procedural anaesthesia).
Proton-pump inhibitors	Risk of Clostridium difficile infection and bone loss.	Avoid prolonged use (unless the patient is high risk, has oesophageal disease, a hypersecretory condition, or a demonstrated need for maintenance therapy).
Non-selective NSAIDs	Increased risk of GI bleeding or peptic ulcer disease. May increase blood pressure and induce kidney injury.	Avoid chronic use
Long-acting sulfonylureas Glimepiride Glibenclamide	Higher risk of severe prolonged hypoglycaemia in older adults.	Avoid

Abbreviations: NSAIDs, non-steroidal anti-inflammatory drugs; CNS, central nervous system; GI, gastrointestinal; CrCl, creatinine clearance.

A number of other medications have been identified as being potentially inappropriate in older adults with specific medical conditions. For example, anticholinesterases should be avoided in older adults with a history of syncope that may be due to bradycardia. Anticholinesterases such as donepezil, galantamine, and rivastigmine can produce vagotonic effects on the heart rate and worsen any pre-existing bradycardia. Other key conditions that warrant particular consideration of PIMs include heart failure, delirium, dementia or cognitive impairment, history of falls or fractures, Parkinson’s disease, history of gastric or duodenal ulcers, chronic kidney disease with a CrCl <30mL/min, urinary incontinence in women, lower urinary tract symptoms, and benign prostatic hyperplasia.

There are also a number of medications identified as being of concern in older adults, but for which the evidence is lacking to support a blanket recommendation to avoid. These agents are classified as drugs to be used with caution in older adults. A summary of these agents can be seen in Table 2.

Table 2. Drugs to be used with caution in older adults

Drug	Rationale	Recommendation	Change from 2015 recommendations
Aspirin (for primary prevention of CV disease and colorectal cancer)	Increased risk of major bleeding from aspirin in older age.	Caution in adults ≥70 years.	Age lowered from 80 years. Criterion expanded to include primary prevention of colorectal cancer.
Dabigatran Rivaroxaban	Increased risk of bleeding compared with warfarin and other DOACs when used for long-term treatment of VTE or AF in adults ≥75 years.	Caution for treatment of VTE or AF in adults ≥75 years.	Rivaroxaban added to the existing entry for dabigatran.
Prasugrel	Increased risk of bleeding in older adults.	Caution in adults ≥75 years.	–
Antipsychotics Carbamazepine Oxcarbazepine Diuretics Antidepressants Mirtazapine SNRIs SSRIs TCAs Tramadol	May exacerbate or cause SIADH or hyponatraemia.	Use with caution, monitor sodium level closely upon initiation or dose changes.	Tramadol added to list Chemotherapeutic agents removed.
Trimethoprim + sulfamethoxazole	Increased risk of hyperkalaemia when used with an ACE-I or ARB in patients with reduced renal function.	Caution in patients taking an ACE-I or ARB with reduced CrCl.	New addition

Abbreviations: CV, cardiovascular; SNRI, serotonin and noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; DOAC, direct-acting oral anticoagulant; VTE, venous thromboembolism; AF, atrial fibrillation; SIADH, syndrome of inappropriate antidiuretic hormone secretion; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor antagonist.

The Beers Criteria make additional considerations of drug interactions to avoid in older people and drugs to avoid or dose modify in older adults with reduced kidney function. Two significant additions to the drug interactions to avoid are the use of opioids with benzodiazepines and the use of opioids with gabapentinoids. Such combinations increase the risk of overdose or the risk of severe sedation-related adverse events such as respiratory depression and death. Recommendations for older adults with renal impairment include reducing the dose of enoxaparin and avoiding spironolactone, which echoes the advice contained in the respective Australian approved product information documents.

Although many of the medication issues described in the Beers Criteria are broadly applicable to patients of all ages, the elderly may be at greater risk of harms. The reasons for this are many and complex, but include physiological changes that affect drug absorption, distribution, metabolism, and excretion, and the greater incidence of polypharmacy in this patient group. The Australian Commission on Safety and Quality in Health Care reports that between 40% and 50% of residents in aged care facilities are prescribed at least one PIM.

Options to reduce the exposure to PIMs include:

• Reduce the number or dose of medications that may be causing harm. Evidence-based deprescribing guidelines can be consulted for further guidance;
• Consider safer alternatives to PIMs (e.g. a second-generation antihistamine may be preferred to a first-generation antihistamine); and
• Consideration of non-pharmacological therapies (e.g. massage, mouth care, animal-assisted therapy).

The Beers Criteria is a useful evidence-based aid that may be used to help assess the appropriateness of pharmacotherapy in older adults. However, it should be emphasised that medications identified in the criteria are potentially inappropriate rather than definitely inappropriate for all older persons. It is also important to note that the criteria was developed for the USA and is not intended to be used in hospice or palliative care settings where risk-benefit considerations may be different. In all cases, it is the clinical judgement of the prescriber in conjunction with the patient’s wishes that should guide decision making.

Many pharmacists at HPS Pharmacies pursue additional education opportunities to further advance their expertise and the level of professional services they provide. One such pharmacist is Dr Shir Ley Tan, Pharmacy Manager at Calvary North Adelaide. HPS Pharmacies is proud to share the intervention protocol developed by Shir Ley and her colleagues which was recently published on the Cochrane Database of Systematic Reviews.

This protocol, entitled Animal‐assisted therapy for dementia, will be used to evaluate the safety and efficacy of animal-assisted therapy for people with dementia. It is estimated that more than 436,000 Australians are currently living with dementia. As this is an age-related disorder, the prevalence of dementia is expected to increase in Australia due to our ageing population.

Dementia is a devastating diagnosis for patients and their families. Initial symptoms may relate to an impaired ability to learn and remember new information. However, the progressive nature of the condition means that patients will often also experience significant declines in abstract thinking, judgement, verbal fluency, orientation, comprehension and the ability to perform complex tasks. Unfortunately, no therapy to date has been found to be clearly and consistently effective in preventing or halting the progression of dementia.

It has been suggested that animal-assisted therapy (AAT) may be able to improve symptoms and possibly also functional abilities in people who have dementia. AAT simply refers to the use of an animal in the treatment of human physical or psychological disorders. It is not a new concept, having been formally introduced in 1969. AAT, using dogs, cats, or aquatic animals, may reduce loneliness and agitation in people with dementia as a result of increased social interaction.

Shir Ley and her colleagues have identified the lack of systematic reviews of randomised controlled clinical trials specifically related to the use of AAT in people with dementia. The analyses to be performed by Shir Ley and her colleagues using their protocol will add to the growing body of data on AAT and dementia. It is anticipated that the results will help guide practice, guideline and policy development, as well as future research.

We look forward to reading the results of this innovative study.

A full text version of the protocol can be accessed at Cochrane Library.

Dosing of drugs in the critically ill can be challenging due to multiple factors such as changes in organ function, multiple comorbidities and other clinical interventions which can change the pharmacokinetics of a drug significantly. While most clinicians are vigilant to dose reduce drugs when there is impaired organ function (e.g. acute kidney injury), less consideration is given to the opposite end of the spectrum – that is, augmented renal clearance (ARC).

What is ARC and how does it happen?

ARC is a state of increased kidney function that results in accelerated clearance of drugs. If no dosage adjustments occur, this may lead to sub-therapeutic levels of medications and subsequent therapy failure. Though there are no standardised cut off points for ARC, generally, it is defined as an increased creatinine clearance (CrCl) of greater than 130mL/min/1.73m².

Although specific literature on ARC remains sparse, ARC has been documented in patients with sepsis, ventilator-associated pneumonia, traumatic brain injury, burns, multi-trauma and post-operatively. The incidence of ARC in the general ICU population is approximately 56% but has been reported to range from 30% in patients after abdominal surgery, to as high as 100% of patients with subarachnoid haemorrhage.

The pathophysiology behind ARC is complicated, and its onset tends to coincide with an acute insult to the body. Simplified, ARC is a hyperdynamic state of renal clearance in which changes to vascular permeability and increased blood flow secondary to elevated body temperature and cardiac output lead to an increase in kidney perfusion and subsequent increases in CrCl. However, there are a number of other factors which are thought to also contribute to ARC including insult to the brain (which may affect cerebral autoregulation of blood pressure, for example) and changes in nephron physiology (e.g. renal tubular reabsorption). Additionally, clinical interventions such as fluid resuscitation and the use of vasoactive drugs further augment this process.

Risk Factors

In general, patients exhibiting ARC tend to be younger (<50 years old), of male gender, have a recent history of trauma, and have lower critical illness severity scores e.g. APACHE II (acute physiology and chronic health evaluation) score or SOFA (sequential organ failure assessment) score. However, young age appears to be the only risk factor that consistently predicts ARC.

Two main methods of identifying patients at risk of ARC have been suggested. The first method is the ARC scoring system which was developed by Udy et al. This method scores a patient based on the risk factors of age, presence of trauma, and SOFA score. The second method to identify ARC was developed by Barletta et al. which eliminated the need to complete a SOFA score. This was called the ARCTIC (augmented renal clearance in trauma intensive care) scoring system. While the ARC scoring system demonstrated greater sensitivity and specificity than the ARCTIC scoring system, the ARCTIC scoring system allows for earlier recognition of ARC in the ICU setting. The scoring systems are shown in Table 1.

Table 1. Comparison of ARC scoring systems

	ARC Scoring System		ARCTIC Scoring System
Criteria	Criteria	Points	Criteria	Points
	Age < 50 years Trauma SOFA score < 4	6 3 1	SCr <62µmol/L Male sex Age <56 years Age: 56-75 years	3 2 4 3
Interpretation	0-6 points = low ARC risk 7-10 points = high ARC risk		<6 points = low ARC risk >6 points = high ARC risk

SCr = serum creatinine concentration; SOFA = sequential organ failure assessment score

Identification of ARC

When it comes to actually identifying whether a patient has ARC, calculating a patient’s glomerular filtration rate (GFR) via inulin clearance is regarded as the gold standard. However, routine monitoring using this method is labour intensive and often not practical. When various mathematical estimates were compared (e.g. Cockcroft Gault equation, the modification of diet in renal diseases formulae, and the chronic kidney disease-epidemiology equation), the Cockcroft Gault equation appeared to be the best method to estimate creatinine clearance in the ARC population.

Duration of ARC

The duration of ARC varies significantly, with some patients exhibiting transient ARC lasting for less than 24 hours, whilst other studies have reported ARC lasting for weeks. As such, continuous monitoring of a patient’s renal function is warranted to appropriately dose-modify renally cleared drugs.

Management and Drug dosing in ARC

In renally cleared drugs, the presence of ARC can lead to enhanced drug clearance – that is, a shorter drug half-life (t½), lower maximum drug concentration (Cmax), and lower area under the concentration curve (AUC). This makes dosing of drugs in ARC challenging, especially for those drugs which do not have measurable endpoints, e.g. antimicrobials. Low levels of antimicrobials can be difficult to detect, as you cannot immediately measure patient response as you might for other drugs, such as sedatives. However, therapy failure with an antimicrobial, especially in settings such as septic shock, can have significant effects on morbidity and mortality. A study which looked at antimicrobial use in patients with ARC found that there was a significant increase in the rate of antibiotic therapeutic failure in patients with ARC (27.3% vs 12.9%), with four patients in the ARC arm developing antibiotic resistance, as opposed to just one patient in the non-ARC group.

For patients with confirmed ARC, dose adjustments should be considered for all renally cleared medications. However, dosing of drugs in ARC is complicated, as drug monographs do not acknowledge the need for alterations to drug dosing regimens in ARC, and there is scant literature on the adjustment of drug dosages in the ARC population. Where possible, therapeutic drug monitoring (TDM) should be utilised to adjust dosages. For medications where TDM is not available, the use of the highest approved dose or most frequent administration could be considered with close clinical monitoring. For example, a suggested dosing for meropenem in an adult with ARC is 2g IV eight-hourly. Changing to alternative medications which are not renally cleared should also always be considered.

The following algorithm has been proposed as a guide for clinicians in managing patients presenting with ARC:

Step 1.

• Find out if 8 to 24-hour urinary measurement of creatinine clearance is readily available
• If yes, does the patient have ARC? If so, go to step 5.
• If no, consider risk factors and the need for measured creatinine clearance

Step 2.

• Assess if the patient has risk factors associated with ARC
• Younger age (<50 years old)?
• Male gender?
• Reason for admission (e.g. traumatic brain injury, subarachnoid haemorrhage, severe infection or sepsis)
• Hemodynamically stable?
• No history of impaired renal function?
• Serum creatinine within normal reference range?

Step 3.

• Is the patient at high ARC risk as per the ARC scoring system?

Step 4.

• Obtain 8 to 24 hour measured creatinine clearance

Step 5.

• Is the patient on renally eliminated medications affected by ARC?
• Is there delayed or insufficient clinical response?
• Do surrogate markers of disease indicate delayed or insufficient clinical response?

Step 6.

• Increase drug dosing or shorten administration regimen
• Consider therapeutic drug monitoring (TDM)
• Consider highest recommended dose or shortest administration regimen
• Consider alternative medications which are not eliminated renally

Step 7.

• Reassess for risk or presence of ARC daily

A biofilm can be defined as a layer of microorganisms adhering to a surface and each other in an aqueous environment. This microbial colony is able to attach to organic or inorganic surfaces by excreting a sticky sugary material called extracellular polymeric substance (EPS). The strand-like structure of EPS can create a complex matrix by binding large numbers of cells together. The biofilm produced by this process may be made up of a single species of microorganism, or a number of different species. The size of the biofilm is also highly variable depending upon environmental conditions. It may be the thickness of a single cell or several centimetres thick and visible to the naked eye. The presence of these highly organised microbial colonies challenges much of the traditional thinking about microbial behaviour.

One of the most studied examples of a biofilm is dental plaque. Plaque is often comprised of a highly diverse range of microbial species. Damage to the teeth can be particularly serious when the balance shifts to species that can readily survive in an acidic environment and produce acidic metabolic by-products. The acids produced by these bacteria can damage teeth enamel once the pH falls below the critical pH for maintenance of enamel mineral content. Selection for these organisms is associated with regular periods of low pH as occurs during sugar catabolism and reduced saliva production.

Whilst dental plaque is a highly visible and accepted cause of morbidity, biofilms are now associated with many chronic and serious infections. The US National Institutes of Health suggest that 65% of all microbial infections and up to 80% of chronic infections are associated with biofilm formation. The high prevalence of biofilms and the fact that we know they behave differently to isolated organisms highlights the importance of understanding this microbial phenomenon.

Why do biofilms form?

Microbes congregated in a biofilm are better able to resist environmental stressors including host immune defences. This equates to a greater chance of survival. The first microbe to adhere to the surface can be termed an early colonist. The attachment of these early colonists is initially very weak. However, if they are not immediately separated from the surface, the attachment becomes more permanent due to a process called cell adhesion. Cell adhesion involves the excretion of substances such as proteins onto the surface of the microbe that facilitates binding of other cells.

During this period of colonisation, it is thought that the microbes are able to communicate with the colony using the phenomenon of quorum sensing. This allows microbes to regulate their gene expression based upon the cell-density of the colony. Interestingly, this communication method can be utilised within a species or between different microbial species and allows the colony to behave as a group.

Diversity within the biofilm has been shown to increase the chances of biofilm success due to reduced competition for the same resources. Studies also demonstrate that cells within a biofilm become more ordered and densely packed as time goes on. This offers additional advantages to the colony by further reducing its ability to be penetrated.

Clinical relevance

Studies demonstrate that biofilm bacteria can be up to a thousand times more resistant to antibiotic stress compared to free-swimming bacteria. There are several proposed reasons for this. Firstly, the EPS is thought to act as a physical barrier with limited permeability to antibiotics. Secondly, the bacteria within a biofilm often enter a phase of reduced metabolic activity and growth. This translates to a reduced sensitivity to antibiotics as the bactericidal activity of many antibiotics depends upon active bacterial metabolism.

The matrix also provides protection to the microbes inside as the host’s immune system is less likely to recognise it and mount an immune response. This makes treating a biofilm infection much more challenging. Microbes may periodically leave the protection of the biofilm at which point the host is likely to recognise the cell and mount an immune response. This may explain the nature of many chronic relapsing infections.

Some conditions thought to involve biofilm formation include:

• Chronic pseudomonal infections in cystic fibrosis;
• Chronic otitis media;
• Chronic sinusitis;
• Chronic prostatitis;
• Toxic shock syndrome;
• Kidney stones;
• Endocarditis; and
• Infections of medical devices (e.g. prosthetic joints, cardiac pacemakers, urinary catheters).

Treatment

Antimicrobial treatment is often insufficient to fully eradicate a biofilm infection. For some biofilm infections, such as chronic lower airways infections in cystic fibrosis, the aim of treatment may be to suppress the infection rather than complete eradication.

Selection of an appropriate antimicrobial agent should consider the sensitivity of the microbe. However, the antimicrobial must also be able to penetrate the biofilm well enough to achieve effective concentrations at the site of infection. The general ability of antibiotics to penetrate a biofilm is displayed in Table 1.

Table 1. Ability of antibiotics to penetrate biofilm

Higher penetration	Lower penetration
Macrolides	Penicillins
Lincosamides	Cephalosporins
Tetracyclines	Carbapenems
Rifamycins	Aminoglycosides
Quinolones	Glycopeptides
Sodium fusidate
Nitroimidazoles
Sulfonamides
Linezolid

Owing to the higher minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) associated with biofilms, higher doses of antibiotics are generally required. However, reaching effective antibiotic levels may not always be possible with conventional administration methods due to the limitations of renal and hepatic function, toxicities, and side effects. Combination therapy with systemic and topical administration may help to overcome this issue and could be suitable for some patients, e.g. antibiotic inhalation for biofilms of the airways or bladder irrigations for urinary biofilms.

Other treatment options that may be used in combination include physical removal of the biofilm (e.g. wound debridement, removal of infected medical devices), use of antimicrobials from different classes, and a prolonged duration of therapy. Research is continuing into the development of anti-quorum sensing medicines to disrupt communication within the biofilm.

Around two in three Australians will be diagnosed with skin cancer by the time they are 70 years of age. This makes sun safety an important public health message. The most recent National Sun Protection Survey, conducted by the Cancer Council, demonstrates that over 90% of Australians do not understand when sun protection is required. This highlights the importance of reinforcing the sun safe message. All Australians should be vigilant to protect themselves from the sun. However, some medications require particular care.

Drug-induced photosensitivity is a reaction that occurs as a result of the effects of a drug combined with light exposure. These reactions can be further divided into phototoxic reactions and photoallergic reactions.

Phototoxic reactions

Phototoxic reactions occur when a photoreactive chemical is transformed into a compound that is cytotoxic to skin cells following activation by light. These reactions tend to present as an exaggerated sunburn response, with erythema and oedema developing within minutes to hours of light exposure. Blistering may occur in more severe reactions, leaving temporary patches of hyperpigmentation after healing. Phototoxic reactions will develop in almost all individuals exposed to sufficient amounts of the chemical and light.

Phototoxic reactions are commonly noted with the quinolone class of antibiotics. However, there is some variation within the class, and minocycline may be less likely to cause a reaction compared to others in the class. Amiodarone is another common cause of phototoxic reactions. Some sources estimate that up to 75% of patients on long-term amiodarone therapy will experience phototoxicity. This medication typically causes prickling or burning sensations during light exposure; higher doses may be associated with oedema and urticaria. A distinctive blue-grey pigmentation can also occur, although this is less common and often limited to people with very pale skin.

Amiodarone is unusual as reactions tend to occur at least four months after therapy is initiated and can even occur months after discontinuation. This is due to its long half-life which is usually 14 to 59 days, but may be as long as 110 days.

Strategies to prevent phototoxic reactions include:

• Avoidance of direct excessive sun exposure;
• Wearing protective clothing when outside; and
• Frequent application of a broad-spectrum sunscreen with a high sun protection factor.

In many cases, drug therapy can continue following a phototoxic reaction provided sun protection is possible. However, an alternative agent may be considered for people with high occupational sun exposure, severe reactions, or reactions that are cosmetically unacceptable.

Photoallergic reactions

In contrast, photoallergic reactions more closely resemble allergic contact dermatitis. Distribution is typically limited to sun-exposed areas of the body, although more severe reactions may extend into covered areas of skin. As the name suggests, photoallergic reactions involve an immune component. In this case, activation of the chemical by light produces a metabolite that can then bind to proteins in the skin to form an antigen. The resulting complex then elicits an immune response. While much smaller quantities of the chemical are required to produce photoallergic reactions, these reactions will only be observed in a minority of individuals exposed to the chemical and light. The onset is often delayed by 24 to 72 hours after exposure.

Some chemical absorbers used in sunscreens can rarely produce photoallergic reactions. These reactions are more commonly associated with benzophenone, butyl methoxy dibenzoylmethane, and para-aminobenzoic acid. If sunscreen is suspected of causing the reaction, a sunscreen containing a physical reflectant such as zinc oxide or titanium dioxide may be considered as a substitute. Physical sunscreens tend to be better tolerated but may leave a white tint on the skin.

Once a photoallergic reaction has been experienced to a particular agent, reactions of increasing severity are possible following minimal amounts of further sun exposure. Therefore, medications suspected of causing a photoallergic reaction should be discontinued.

A general summary of the differences between phototoxic and photoallergic reactions can be seen in Table 1.

Table 1. Features of phototoxic and photoallergic reactions

Feature	Phototoxic reaction	Photoallergic reaction
Incidence	High	Low
Dose required	Large	Small
Onset	Minutes to hours	24-72 hours
Reaction with first exposure	Yes	No
Distribution	Sun-exposed skin	May spread to covered areas of skin
Characteristics	Exaggerated sunburn	Contact dermatitis
Immune-mediated	No	Yes

 Immunosuppressants

Some medications that do not cause photosensitivity also contain patient warnings to minimise sun exposure. Immunosuppressants may increase the risk of developing skin cancer by impairing the immune system network in the skin, reducing its ability to detect and respond against skin cancer. Studies demonstrate that 15% to 40% of patients will develop skin cancers within the first ten years of receiving a kidney transplant and up to 82% will develop skin cancer within 20 years. The level of increased risk appears to be more highly associated with the degree and duration of immunosuppression rather than the individual immunosuppressants used.

Table 2 lists the medications identified by the Australian Pharmaceutical Formulary and Handbook as requiring a warning to avoid excessive sun exposure.

Table 2. Medications that require a warning to avoid excessive sun exposure

Medications	Proposed reason for caution
Antimicrobials
Doxycycline	Phototoxic
Ciprofloxacin
Norfloxacin
Trimethoprim with sulfamethoxazole
Voriconazole
Griseofulvin	Phototoxic, photoallergic
Neuroleptics
Chlorpromazine	Phototoxic, photoallergic
Fluphenazine
Thioridazine
Olanzapine	Phototoxic
Zuclopenthixol
Trifluoperazine
Dermatologicals
Acitretin	Phototoxic
Adapalene
Isotretinoin
Tretinoin
Calcipotriol
Kinase inhibitors
Afatinib	Phototoxic
Alectinib
Dabrafenib
Imatinib
Vemurafenib
Cobimetinib	In vitro tests suggest phototoxic, no clinical evidence with use as a single agent
Erlotinib	Phototoxic, photoallergic
Vandetanib
Cytotoxic antineoplastics
Dacarbazine	Phototoxic
Tioguanine
Mercaptopurine
Methotrexate
Fluorouracil	Phototoxic, photoallergic
Others
Fenofibrate	Phototoxic, photoallergic
Flutamide
Hydroxychloroquine	Photoallergic – sunglasses should also be worn to reduce risk of retinopathy
Imiquimod	Mechanism not established – enhances UV carcinogenicity in animal models
Amiodarone	Phototoxic
Danazol
Dantrolene
Demeclocycline
Clofazimine
Immunosuppressants
Ciclosporin	Immunosuppression
Tacrolimus
Everolimus
Sirolimus
Azathioprine
Mycophenolate/mycophenolic acid

Management

Photosensitivity reactions can be difficult to predict. Patients taking medications with the potential to cause photosensitivity should be educated on appropriate measures to avoid reactions. Treatment of photosensitivity reactions is symptomatic; topical corticosteroids and cool compresses may provide some relief. Avoidance of the causative agent may also be required.

Patients taking immunosuppressants should also be advised to limit their sun exposure. Regular skin checks should be performed so that any abnormalities are detected early.