Knowledge Type: Clinical Articles

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.