One of the growing community healthcare delivery agendas is that of the advanced nurse practitioner (ANP) role to improve access to timely, appropriate assessment and treatment of patients, in an attempt to avoid unnecessary health deterioration and/or hospitalisation (O'Neill et al, 2021). The Core Capabilities Framework for Advanced Clinical Practice (Nurses) Working in General Practice/Primary Care in England recognises the application of essential skills, including sound consultation and clinical decision making for prescribing appropriate treatment (Health Education England [HEE], 2020). This article will discuss and reflect on a case study involving the prescribing of nitrofurantoin by a ANP for a suspected symptomatic uncomplicated urinary tract infection (UTI), in a patient living in a care home. Focus will be around the consultation and decision-making process of non-medical prescribing and will explore and critique the evidence-base, examining the local and national guidelines and primary research around the pharmacokinetics and pharmacodynamics of nitrofurantoin. Consideration of the legal, ethical and professional issues when prescribing in a non-medical capacity will also be sought, concluding with review of the continuing professional development required to influence future prescribing decisions relating to the case study.
Case study
Mrs M, an 87-year-old lady living in a nursing home, was referred to the community ANP by the senior carer. The presenting complaint was reported as dark, cloudy, foul-smelling urine, with new confusion and night-time hallucinations. The carer reported a history of disturbed night sleep, with hallucinations of spiders crawling in bed, followed by agitation, lethargy and poor oral intake the next morning. The SBAR (situation, background, assessment, recommendation) tool was adopted, ensuring structured and relevant communication was obtained (NHS England and NHS Improvement, 2021). The National Institute for Health and Care Excellence (NICE, 2021) recognises that cloudy, foul-smelling urine may indicate UTI. Other symptoms include increased frequency or pressure to pass urine, dysuria, haematuria or dark coloured urine, mild fever, night-time urination, and increased sweats or chills, with lower abdominal/loin pain suggesting severe infection. NICE (2021) highlight that patients with confusion may not report UTI symptoms. This is supported by Gupta and Gupta (2019), who recognise new confusion as hyper-delirium, which can be attributed to several causative factors including infection, dehydration, constipation and medication, among others.
UTIs are one of the most common infections worldwide (O'Grady et al, 2019). Lajiness and Lajiness (2019) define UTI as a presence of colonising bacteria that cause a multitude of symptoms affecting either the upper or lower urinary tract. NICE (2021) further classifies UTIs as either uncomplicated or complicated, with complicated involving other systemic conditions or pre-existing diseases. Geerts et al (2013) postulate around 30% of females will develop a UTI at least once in their life. The incidence increases with age, with those over 65 years of age being five times more likely to develop a UTI at any point. Further increased prevalence is found in patients who live in a care home, with up to 60% of all infections caused by UTI (Bardsley, 2017).
Greener (2011) reported that symptoms of UTIs are often underestimated by clinicians. A study cited by Greener (2011) found over half of GPs did not record the UTI symptoms that the patient had reported. It is, therefore, essential during the consultation to use open-ended questions, listening to the terminology of the patient or carers to clarify the symptoms and creating an objective history (Taylor, 2016).
In this case, the carer highlighted that Mrs M had been treated for suspected UTI twice in the last 12 months. Greener (2011), in their literature review of 8 Cochrane review papers and 1 systematic review, which looked at recurrent UTI incidences in general practice, found 48% of women went on to have a further episode within 12 months.
Mrs M's past medical history reviewed via the GP electronic notes included:
- Hypertension
- Diverticular disease
- Basal cell carcinoma of scalp
- Retinal vein occlusion
- Severe frailty
- Fracture of proximal end of femur
- Total left hip replacement
- Previous indwelling urinary catheter
- Chronic kidney disease (CKD) stage 2
- Urinary and faecal incontinence
- And, most recently, vesicovaginal fistula.
Bardsley (2017) identified further UTI risk factors including postmenopausal females, frailty, co-morbidity, incontinence and use of urethral catheterisation. Vesicovaginal fistulas also predispose to recurrent UTIs, due to the increase in urinary incontinence (Stamatokos et al, 2014). Moreover, UTIs are common in older females living in a care home (Bradley and Sheeran, 2017). They can cause severe risks to the patient if left untreated, leading to complications such as pyelonephritis or sepsis (Ahmed et al, 2018).
Mrs M's medication included:
- Paracetamol 1 g as required
- Lactulose 10 ml twice daily
- Docusate 200 mg twice daily
- Epimax cream
- Colecalciferol 400 units daily
- Alendronic acid 70 mg weekly.
She did not take any herbal or over the counter preparations. Her records reported no known drug allergies; however, she was allergic to Elastoplast. A vital part of clinical history involves reviewing current prescribed and non-prescribed medications, herbal remedies and drug allergies, to prevent contraindications or reactions with potential prescribed medication (Royal Pharmaceutical Society, 2019). Several authors, including Malcolm et al (2018), indicate polypharmacy as a common cause of adverse drug reactions (ADRs), worsening health and affecting a person's quality of life. NICE (2015) only recommends review of patients who are on four or more medications on each new clinical intervention, not taking into account individual drug interactions.
Due to Mrs M's lack of capacity, her social history was obtained via the electronic record and the carer. She moved to the care home 3 years ago, following respite care after her fall and hip replacement. She had never smoked or drank alcohol. Documented family history revealed stroke, ischaemic heart disease and breast cancer. Taylor (2016) reports a good thorough clinical history can equate to 90% of the working diagnosis before examination, potentially reducing unnecessary tests and investigations. This can prove challenging when the patient has confusion. It takes a more investigative approach, gaining access to medical/nursing care notes, and using family or carers to provide further collateral history (Gupta and Gupta, 2019).
As per NICE (2021) guidelines, a physical examination of Mrs M was carried out. On examination it was noted that Mrs M had mild pallor with normal capillary refill time, no signs of peripheral or central cyanosis, and no clinical stigmata to note. Her heart rate was elevated at 112 beats per minute and regular, she had a normal respiration rate of 17 breaths per minute, oxygen saturations (SpO2) were 98% on room air and blood pressure was 116/70 mm/Hg. Her temperature was 37.3oC. According to Doyle and Schortgen (2016), there is no agreed level of fever; however, it becomes significant when above 38.3oC. Bardsley (2017) adds that older patients do not always present with pyrexia in UTI because of an impaired immune response.
Heart and chest sounds were normal, with no peripheral oedema. The abdomen was non-distended, soft and non-tender on palpation, with no reports of nausea, vomiting, supra-pubic tenderness or loin pain. Loin pain or suprapubic tenderness can indicate pyelonephritis (Bardsley, 2017). Tachycardia, fever, confusion, drowsiness, nausea/vomiting or tachypnoea are strong predictive signs of sepsis (NICE, 2021).
During the consultation, confusion and restlessness were evident. Therefore, it was difficult to ask direct questions to Mrs M regarding pain, nausea and dizziness. Non-verbal cues were considered, as changes in behaviour and restlessness can potentially highlight discomfort or pain (Swift, 2018).
Mrs M's most recent blood tests indicated CKD stage 2, based on an estimated glomerular filtration rate (eGFR) of 82 ml/minute/1.73m2. The degree of renal function is vital to establish prior to any prescribing decision, because of the potential increased risk of drug toxicity (Doogue and Polasek, 2013). The agreed level of mild renal impairment is when eGFR is <60 ml/minute/1.73 m2, with chronic renal impairment established when eGFR levels are sustained over a 3-month period (Ahmed et al, 2018).
Previous urine samples of Mrs M grew Escherichia coli bacteria, sensitive to nitrofurantoin but resistant to trimethoprim. A consensus of papers, including Lajiness and Lajiness (2019), highlight the most common pathogen for UTI as E. coli. Fransen et al (2016) indicates that increased use of empirical antibiotics has led to a prevalence of extended spectrum beta lactamase positive (ESBL+) bacteria that are resistant to many current antibiotics. This is not taken into account by the NICE guidelines (2021); however, it is discussed in local guidelines (Barnsley Hospital NHS FT/Rotherham NHS FT, 2022).
Mrs M was unable to provide an uncontaminated urine sample due to incontinence. NICE (2021) advocate urine culture as a definitive diagnostic tool for UTIs; however, do not highlight how to objectively obtain this. Bardsley (2017) recognises the benefit of an uncontaminated urinalysis in symptomatic patients, stating that alongside other clinical signs, nitrates and leucocytes strongly predict the possibility of UTI. O'Grady et al (2019) points out that although NICE emphasise urine culture collection, it omits the use of urinalysis as part of the assessment.
Based on Ms M's clinical history and physical examination, a working diagnosis of suspected symptomatic uncomplicated UTI was hypothesised. A decision was made, based on the local antibiotic prescribing guidelines, as well as the NICE (2021) guidelines, to treat empirically with nitrofurantoin modified release (MR), 100 mg twice daily for 3 days, to avoid further health or systemic complications. The use of electronic prescribing was adopted as per local organisational policy and the Royal Pharmaceutical Society (2019). Electronic prescribing is essential for legibility and sharing of prescribing information. It also acts as an audit on prescribing practices, providing a contemporaneous history for any potential litigation (Lovatt, 2010).
Pharmacokinetics and pharmacodynamics
Lajiness and Lajiness (2019) reflect on the origins of nitrofurantoin back to the 1950s, following high penicillin usage leading to resistance of Gram-negative bacteria. Nitrofurantoin has been the first-line empirical treatment for UTIs internationally since 2010, despite other antibacterial agents being discovered (Wijma et al, 2020). Mckinell et al (2011) highlight that a surge in bacterial resistance brought about interest in nitrofurantoin as a first-line option. Their systematic review of the literature indicated through a cost and efficacy decision analysis that nitrofurantoin was a low resistance and low cost risk; therefore, an effective alternative to trimethoprim or fluoroquinolones. The weakness of this paper is the lack of data on nitrofurantoin cure rates and resistance studies, demonstrating an inability to predict complete superiority of nitrofurantoin over other antibiotics. This could be down to the reduced use of nitrofurantoin treatment at the time.
Fransen et al (2016) reported that minimal pharmacodynamic knowledge of nitrofurantoin exists, despite its strong evidence-based results against most common urinary pathogens, and being around for the last 70 years. Wijma et al (2018) hypothesised this was because of the lack of drug approval requirements in the era when nitrofurantoin was first produced, and the growing incidence of antibiotic resistance. Pharmacokinetics and pharmacodynamics are clinically important to guide effective drug therapy and avoid potential ADRs. Focus on the absorption, distribution, metabolism and excretion (ADME) of nitrofurantoin is needed to evaluate the correct choice for an individual patient, based on a holistic assessment (Doogue and Polasek, 2013).
Nitrofurantoin is structurally made up of 4 carbon and 1 oxygen atoms forming a furan ring, connected to a nitrogroup (–NO2). Its mode of action is predominantly bacteriostatic, with some bactericidal tendencies in high concentration levels (Wijma et al, 2018). It works by inhibiting bacterial cell growth, breaking down its strands of DNA (Komp Lindgren et al, 2015). Hoang and Salbu (2016) add that nitrofurantoin causes bacterial flavoproteins to create reactive medians that halt bacterial ribosomal proteins, rendering DNA/RNA cell wall synthesis inactive.
Nitrofurantoin is administered orally via capsules or liquid. Greener (2011) highlights the different formulations, which originally included microcrystalline tablets and now include macro-crystalline capsules. The increased size of crystals was found to slow absorption rates down (Hoang and Salbu, 2016). Nitrofurantoin is predominantly absorbed via the gastro-intestinal tract, enhanced by an acidic environment. It is advised to take nitrofurantoin with food, to slow down gastric emptying (Wijma et al, 2018). The maximum blood concentration of nitrofurantoin is said to be <0.6 mg/l. Lower plasma concentration equates to lower toxicity risk; therefore, nitrofurantoin is favourable over fluoroquinolones (Komp Lindgren et al, 2015). Wijma et al (2020) found a reduced effect on gut flora compared to fluoroquinolones.
Distribution of nitrofurantoin is mainly via the renal medulla, with a renal bioavailability of 38.8–44%; therefore, it is specific for urinary action (Hoang and Salbu, 2016). Haasum et al (2013) highlight the inability for nitrofurantoin to penetrate the prostate where bacteria concentration levels can be present. Therefore, they do not advocate the use of nitrofurantoin to treat males with UTIs, because of the risk of treatment failure and further complications of systemic infection. This did not appear to be addressed by local guidelines.
The metabolism of nitrofurantoin is not completely understood; however, Wijma et al (2018) indicate several potential metabolic antibacterial actions. Around 0.8–1.8% is metabolised into aminofurantoin, with 80.9% other unknown metabolites (medicines.org, 2022). Wijma et al (2020) calls for further study into the metabolism of nitrofurantoin to aid understanding of the pharmacodynamics.
Excretion of nitrofurantoin is predominantly via urine, with a peak time of 4–5 hours, and 27–50% excreted unchanged in urine (medicines.org, 2022). Komp Lindgren et al (2015) equates the fast rates of renal availability and excretion to lower toxicity risks and targeted treatment for UTI pathogens. Wijma et al (2018) found high plasma concentration levels of nitrofurantoin in renal impairment. Singh et al (2015) indicate that nitrofurantoin is mainly eliminated via glomerular filtration; therefore, its impairment presents the potential risks of treatment failure and increased ADRs. Early guidelines stipulated the need to avoid nitrofurantoin in patients with mild renal impairment, indicating the need for an eGFR of >60 ml/min due to this toxicity risk. This was based on several small studies, cited by Hoang and Salbu (2016), looking at concentration levels rather than focused on patient treatment outcomes.
Primary research by Geerts et al (2013) involving treatment outcomes in a large cohort study, led to guidelines changing the limit to mild to moderate impairment or eGFR >45 ml/min. However, the risk of ADRs, including pulmonary fibrosis and hepatic changes, were increased in renal insufficiency with prolonged use. The study participants had a mean age of 47.8 years; therefore, the study did not indicate the effects on older patients. Singh et al (2015) presented a Canadian study, looking at treatment success with nitrofurantoin in older females, with a mean age of 79 years. It indicated effective treatment despite mild/moderate renal impairment. It did not address the levels of ADRs or hospitalisation. Ahmed et al (2018) conducted a large, UK-based, retrospective cohort study favouring use of empirical nitrofurantoin in the older population with increased risk of UTI-related hospitalisation and mild/moderate renal impairment. It concluded not treating could increase mortality and morbidity. This led to guidelines to support empirical treatment of symptomatic older patients with nitrofurantoin.
Dosing is highly variable between the local and national guidelines. Greener (2011) highlights that product information for the macro-crystalline capsules recommends 50–100 mg 4 times a day for 7 days when treating acute uncomplicated UTI. Local guidelines from Barnsley Hospital NHS FT/Rotherham NHS FT Adult antimicrobial guide (2022) stipulate 50–100 mg 4 times daily for 3 days for women, whereas NICE (2021) recommends a MR version of 100 mg twice daily for 3 days.
In a systematic literature review on the pharmacokinetics of nitrofurantoin, Wijma et al (2018) found that use of a 5–7 day course had similar strong efficacy rates, whereas 3 days did not, potentially causing treatment failure, equating to poor patient outcomes and resistant behaviour. Deresinski (2018) conducted a small, randomised controlled trial involving 377 patients either on nitrofurantoin MR 100 mg three times a day for 5 days or fosfomycin single dose treatment after urinalysis and culture. It looked at response to treatment after 28 days. Nitrofurantoin was found to have a 78% cure rate compared to 50% with fosfomycin. Therefore, these studies directly contradict current NICE and local guidelines on treatment dosing of UTI in women. More robust studies on dosing regimens are therefore required.
Fransen et al (2016) conducted a non-human pharmacodynamics study looking at time of action to treat on 11 strains of common UTI bacteria including two ESBL+. It demonstrated the kill rate for E. coli was 16–24 hours, slower than Enterobacter cloacae (6–8 hours) and Klebsiella pneumoniae (8 hours). The findings also indicated that nitrofurantoin appeared effective against ESBL+. Dosing and urine concentrations were measured, and found that 100 mg every 6 hours kept the urine concentration levels significant enough to reach peak levels. This study directly contradicted the findings of Lindgren et al (2015), who conducted similar non-human kinetic style kill rate studies, and found nitrofurantoin's dynamic action to be within 6 hours for E. coli. Both studies have limitations in that they did not take into account human immune response effects.
Wijma et al (2020) highlighted inconsistent dosing regimens in their retrospective audit involving 150 patients treated for UTIs across three Australian secondary care facilities. The predominant dosing of nitrofurantoin was 100 mg twice daily for 5 days for women and 7 days for males. Although a small audit-based paper, it creates debate regarding the lack of clarity around the correct dosing, leaving it open to error. It therefore requires primary research into the follow up of cure rates on guideline prescribing regimens. Dose and timing remains an important issue to reduce treatment failure. It indicates the need for bacteria-dependant dosing, which currently NICE (2021) does not discuss.
Haasum et al (2013) found poor adherence to guidelines for choice and dosing in elderly patients in their Swedish register-based large population study. It highlighted high use of trimethoprim in frail older care home residents, despite guidelines recommending nitrofurantoin as first-line. A recent retrospective, observational, quantitative study by Langner et al (2021) involving 44.9 million women treated for a UTI in the USA across primary and secondary care, found an overuse of fluoroquinolones and underuse of nitrofurantoin and trimethoprim, especially by primary care physicians for older Asian and socio-economically deprived patients. Both these studies did not seek a true qualitative rationale for choices of antibiotics; therefore, limiting the findings.
Legal and ethical considerations
NMP regulation of best practice is set by the Royal Pharmaceutical Society framework (2019), incorporating several acts of law including the medicines act 1968, and medicinal products prescribed by the Nurses Act (1992). As per Nursing Midwifery Council (2021) Code of Conduct and Health Education England (2020), ANPs have a duty of care to patients, ensuring that they work within their area of competence and recognise any limitations, demonstrating accountability for decisions made (Lovatt, 2010).
Empirical treatment of UTIs is debated in the literature. O'Grady et al (2019) summarises that empirical treatment can reduce further UTI complications that can lead to acute health needs and hospitalisation, without increased risk of antibiotic resistance. Greener (2011) states that uncomplicated UTIs can be self-limiting; therefore, not always warranting antibiotic treatment if sound self-care advice is adopted. Chardavoyne and Kasmire (2020) discuss delayed prescribing, involving putting the onus on the patient and carers, which was not advisable in the case of Mrs M. Bradley and Sheeran (2017) found that three quarters of antibiotics in care home residents were prescribed inaccurately, hence recommended a watch and wait approach to treatment in the older care home resident, following implementation of a risk reduction strategy.
Taylor (2016) recommended an individual, holistic approach, incorporating ethical considerations such as choice, level of concordance, understanding and agreement of treatment choice. This can prove difficult in a case such as Mrs M. If a patient is deemed to lack capacity, a decision to act in the patient's best interest should be applied (Gupta and Gupta, 2019). Therefore, understanding a patient's beliefs and values via family or carers should be explored, balancing the needs and possible outcomes. The principle of non-maleficence should be adopted, looking at risks versus benefits on prescribing the antibiotic to the individual patient (Royal Pharmaceutical Society, 2019).
Non-pharmacological advice was provided to the carers to ensure that Mrs M maintained good fluid intake of 2 litres in 24 hours. NICE (2021) advocates the use of written self-care advice leaflets that have been produced to educate patients and/or carers on non-pharmacological actions, supporting recovery and improving outcomes. The use of paracetamol for symptoms of fever and/or pain was also recommended for Mrs M. Prevention strategies proposed by Lajiness and Lajiness (2019) included looking at the benefits of oestrogen cream in post-menopausal women in reducing the incidence of UTIs. Cranberry juice, probiotics and vitamin C ingestion are not supported by any strong evidence base.
There is a duty of care to ensure that follow up of the patient during and after treatment is delivered by the NMP (Chardavoyne and Kasmire, 2020). Clinical safety netting advice was discussed with the carers to monitor Mrs M for any deterioration, and to seek further clinical review urgently. Particular attention to signs of ADRs and sepsis, and the need for 999 response if these occurred, was advocated. A treatment plan was also sent to the GP to ensure sound communication and continuation of safe care (Taylor, 2016).
Professional development issues
The extended role of prescribing brings additional responsibility, with onus on both the NMP and the employer vicariously, to ensure key skills are updated. This is where continued professional development involving research, training and knowledge is sought and applied, using evidence-based, up-to-date practice (HEE, 2020). Adoption of antibiotic stewardship is highlighted by several papers including Lajiness and Lajiness (2019). They advise nine points to consider, to increase knowledge around the actions and consequences of the drug by the prescriber. Despite no acknowledgment in NICE (2021) guidance, previous results of infections and sensitivities are also proposed as vital in antibiotic stewardship.
The use of decision support tools, proposed by Malcolm et al (2018), involves an audit approach looking at antibiograms, that highlight local microbiology resistance patterns to aid antibiotic choices, alongside a risk reduction team strategy. Bradley and Sheeran (2017) looked at improving antibiotic use for UTI treatment in a care home in Pennsylvania. They employed a programme of monitoring and educating clinical staff, patients, carers and relatives in evidence-based self-care and clinical assessment skills over a 30-month period. It demonstrated a reduction in inappropriate antibiotic prescribing, and an improvement in monitoring symptoms and self-care practices, creating better patient outcomes. It was evaluated highly by nursing staff, who reported a sense of autonomy and confidence involving team work. Langner et al (2021) calls for further education and feedback to prescribers, involving pharmacists and microbiology data to identify and understand patterns of prescribing.
Conclusion
UTIs can be misdiagnosed and under- or over-treated, despite the presence of local and national guidelines. Continued monitoring of nitrofurantoin use requires priority, due to its first-line treatment status internationally, as this may increase reliance and overuse of the drug, with potential for resistant strains of bacteria becoming prevalent.
Diligent clinical assessment skills and prescribing of appropriate treatment is paramount to ensure risk of serious complications, hospitalisation and mortality are reduced, while quality of life is maintained. The use of competent clinical practice, up-to-date evidence-based knowledge, good communication and understanding of individual patient needs, and concordance are essential to make sound prescribing choices to avoid harm. As well as the prescribing of medications, the education, monitoring and follow-up of the patient and prescribing practices are equally a vital part of the autonomous role of the NMP.
KEY POINTS:
- Urinary tract infections (UTIs) can be misdiagnosed and under- or over-treated, despite the presence of local and national guidelines
- The incidence of UTI increases with age, with those over 65 years of age being five times more likely to develop a UTI at any point
- Nitrofurantoin has been the first-line empirical treatment for UTIs internationally since 2010. Its mode of action is predominantly bacteriostatic, with some bactericidal tendencies in high concentration levels
- Diligent clinical assessment skills and prescribing of appropriate treatment is paramount to ensure risk of serious complications, hospitalisation and mortality are reduced, while quality of life is maintained
CPD REFLECTIVE PRACTICE:
- How can a good clinical history be gained if the patient lacks capacity?
- What factors need to be considered when safety netting in cases like this?
- What non-pharmacological advice would you give to a patient with a urinary tract infection (or their carers)?
- How will this article change your clinical practice?