Changing the culture of fluoroquinolone prescribing

Fluoroquinolone antibiotics have been around since the late 1980s, but increasing reports of disabling and irreversible side effects associated with them prompted the UK drug regulator to restrict their use in 2019​[1,2]​.

However, with around 38,000 systemic fluoroquinolones still being prescribed by GPs in England each month (as of November 2023), the government is looking to take further measures to limit prescribing​[3]​.

“Despite everyone’s best efforts, the numbers are stubbornly stable,” says Graham Stretch, president of the Primary Care Pharmacy Association.

Fluoroquinolones are a class of broad-spectrum antibiotics providing a wide range of coverage against both gram-positive and gram-negative organisms. However, they can cause permanent musculoskeletal side effects, such as tendonitis and tendon rupture, as well as psychiatric disorders, including depression, suicidal thoughts or suicide attempts​[4,5]​.

The number of reports of suspected musculoskeletal side effects associated with ciprofloxacin, the most used fluoroquinolone, are at an all-time high, with 197 reports submitted to the Medicines and Healthcare products Regulatory Agency’s (MHRA’s) Yellow Card scheme in 2023, detailing 342 potential musculoskeletal reactions (see Figure 1)​[6]​.

In January 2024, the MHRA introduced new restrictions for systemic fluoroquinolones, in its third drug safety update on the antibiotics in the past six months.

As the regulator clamps down on use of fluoroquinolones, a multi-agency group consisting of NHS England, the UK Health Security Agency (UKHSA) and National Institute for Health and Care Excellence (NICE), is working towards finding suitable alternatives to treat common infections.

Concerns

There are currently five systemic fluoroquinolones licensed in the UK — ciprofloxacin, delafloxacin, levofloxacin, moxifloxacin and ofloxacin — available orally, intravenously and via inhalation.

Fluoroquinolones exhibit their antimicrobial activity by inhibiting type II and IV topoisomerase, which is required for bacterial DNA replication, transcription, repair and recombination​[7]​.

Ciprofloxacin is the most prescribed fluoroquinolone and is particularly used to treat gram-negative infections​[8,9]​. Newer generation agents, such as levofloxacin and moxifloxacin, also display good activity against gram-positive bacteria​[9]​.

Fluoroquinolones are used to treat a range of infections, including urinary tract, pyelonephritis, prostatitis and respiratory infections​[9]​. As of January 2024, the antibiotic class features in 13 NICE guidelines (See Box 1).

“They are brilliant drugs and they revolutionised healthcare when they were launched in the late 1980s,” says Philip Howard, antimicrobial stewardship lead at NHS England North East and Yorkshire, and visiting professor at the University of Leeds.

“Over that 30-year period, rare, but serious and potentially long-lasting, side effects have been evolving.”

The first report of tendinopathy associated with fluoroquinolones was published in New Zealand in 1983​[10]​. Since then, the dose-dependent adverse drug reaction has been well documented within the class​[10,11]​.

Fluoroquinolones are known to have an affinity for connective tissue and shown to have a negative effect on collagen fibrils in the tendons​[12–14]​. However, the exact mechanism of action for fluoroquinolone-induced tendinopathy is uncertain​[14]​.

“As we’re learning more and more about these drugs, we’re also learning there are potentially more risks with them, but this needs to be balanced against their benefit,” says Howard.

There are also concerns around antimicrobial resistance resulting from fluoroquinolone use. Under the World Health Organization’s (WHO’s) 2021 ‎AWaRe (access, watch, reserve) classification‎, fluoroquinolones are classified in the ‘watch’ group, meaning they have a high risk of bacterial resistance and should only be prescribed as essential first- or second-line options in a limited number of infections.

“There are three categories: access, watch, and reserve, based on their resistance potential,” explains Elisha Zafar, specialist infection pharmacist at King’s College Hospital NHS Foundation Trust.

“Now, our whole aim in hospital is to use more access antibiotics and reduce on the watch [and] reserve antibiotics.

“Hence why, when fluoroquinolones got put on to the watch category, many hospitals removed them from their guidelines to try to limit their use,” she says.

Prescribing trends

In a drug safety update, published in March 2019, the MHRA introduced the first restrictions on the use of fluoroquinolones, stating that they should not be prescribed for mild-to-moderate or self-limiting infections, or non-bacterial conditions, such as non-bacterial (chronic) prostatitis​[2]​. It warned that patients who: are aged older than 60 years; have renal impairment; have had solid-organ transplantation; or are being treated with a corticosteroid, are at higher risk of tendon damage.

Following the warning, the number of prescriptions for fluoroquinolones issued in primary care in England continued to slowly decline, but appears to have plateaued since April 2021 (see Figure 2).

The latest figures for fluoroquinolone antibiotics show there were 37,969 items prescribed across GP surgeries in England in November 2023​[3]​. According to Howard, this number is estimated to be larger in hospitals, with 5 million patient-days of fluoroquinolones given annually, which equates to around 41,700 10-day courses each month.

In August 2023, the MHRA published a reminder of the risks of fluoroquinolone use, following results of a study led by the European Medicines Agency, which showed no evidence of a change in fluoroquinolone prescribing patterns in the UK since publication of the 2019 restrictions​[15,16]​.

The retrospective population-based cohort study, published in March 2023, reported that, although there was around a 25% reduction in primary care fluoroquinolone prescriptions in the UK between 2016 and 2021, prescribing was already declining before the 2019 regulatory interventions were made​[16]​.

Zafar believes the reason for the slow decline in prescribing is because of difficulties in changing prescribing behaviour among doctors.

“Changing prescribing patterns is really hard because it needs a culture change,” she says.

“Fluoroquinolones are good agents and cover quite a lot of organisms, but it is kind of a trade off when we’re talking about complex infections and the risk of using fluoroquinolones.”

She explains that, in an ideal world, patients are started on a broad-spectrum antibiotic before being switched to a narrow-spectrum antibiotic, once the results of antimicrobial tests come back.

“This doesn’t happen as often as we want it to, that’s why we [pharmacists] are here, and we’re trying to improve that,” she says.

Reg Rehal, advanced clinical pharmacist at the Peartree Surgery and West Horndon Surgery in Essex, believes medicines safety issues need to be better communicated to primary care networks and GP surgeries.  

“I think it’s more to do with old practising ways; people will jump to an antibiotic straightaway because, from their own knowledge, that’s what they have always used, and maybe the communications [on restrictions] are not as clear,” he says.

“It’s on the government websites, but how often do clinicians look at these websites? Unfortunately, I think much of the information [on fluoroquinolones] is probably getting a bit lost.”

New recommendations

The MHRA restrictions published in January 2024, state that, in addition to the limitations implemented so far, fluoroquinolones must only be prescribed when other first-line antibiotics are inappropriate, including when they have failed, will not work because of antibiotic resistance, or are unsafe to use for an individual patient​[4]​.

Rehal is supportive of these restrictions. “By changing fluoroquinolones to second line, it brings a stronger message to ICBs [integrated care boards] and the medicines management teams.

“The guidelines are very clear now. Before 2024, we had a warning; now, we’re in concrete territory not to go near it,” says Rehal.

The Pharmaceutical Journal asked the MHRA why the new restrictions were issued, given that prescription numbers have not increased.

In its response, the UK regulator referred back to its statement, which said that further restrictions have been introduced in response to “increasing Yellow Card reports from patients who have experienced long-lasting or disabling reactions following use of fluoroquinolones, in some cases prescribed for mild to moderate or self-limiting infections, or non-bacterial conditions”​[17]​.

Rehal says that the increasing reports of fluroquinolone-induced tendon disorders may be owing to improved Yellow Card reporting in recent years.

He also emphasises the need for a national audit to review whether the antibiotics are being prescribed correctly.

“That’s the only way I think we’re going to get meaningful data on appropriate prescribing.

“And it probably requires some strong retrospective studies on previous prescribing over the years to assess the trends.

“It’s a lot of work, but it’s the driver to bring these [interventions] into action,” adds Rehal.

While the new restrictions are a positive step towards improving patient safety, they have significant implications in clinical practice and for NICE guidelines.

“[Fluoroquinolones] are the only class of oral antibiotics with activity against pseudomonal infections,” says Howard. Pseudomonas is a gram-negative bacteria that is resistant to a variety of antibiotics​[18]​. He highlights that certain immunocompromised patient groups are more likely to have pseudomonas infections and, to treat this in the community, fluroquinolones are often the only oral option.

“It’s got really good data that it works and covers pseudomonas,” he says, adding that “the best drug that’s been available for people who have pyelonephritis, with all of the evidence, has always been ciprofloxacin”.

“The NICE guidance [for pyelonephritis] provides the option to use cefalexin, although that doesn’t cover pseudomonas infections.” However, pseudomonas infections are uncommon in primary care, he adds.

Howard says one of the options to improve patient safety and reduce antimicrobial resistance with all antibiotics is by reducing the treatment course length from seven to five days, where the evidence supports this. But the use of intravenous (IV) alternatives may require patients to stay in hospital for longer or receive IV antibiotics at home, which will rely on primary care staff to administer the antibiotics.

“This is why we need alternatives that cover pseudomonas,” says Howard.

Incentivising antibiotic development

As the number of adverse reactions increases and the fight against antimicrobial resistance continues, there is a desperate need for development of new antibiotics. Financially, this requires substantial investment from manufacturers. Howard explains that it costs around US$5bn to bring a new antibiotic to the market.

In addition, because new antibiotics will only be prescribed sparingly to preserve their effectiveness for as long as possible, manufacturers do not generally make a profit until the final year of their 20-year patent for a drug, presenting an expensive global barrier.

To combat this, in June 2022, NHS England announced a world-first pilot of a subscription deal to incentivise the pharmaceutical industry to develop new antibiotics​[19]​.

The pilot deal included two antimicrobial drugs, cefiderocol and ceftazidime-avibactam, where the manufacturers received fixed annual payments, primarily based on the availability of the drugs and their value to the NHS, as opposed to the volume used.

NHS England announced in July 2023 that the subscription-style drug contracts will be expanded, which will allow manufacturers to receive annual payments ranging from £10–20m per year if they meet clinically-based criteria​[20]​.

“We’re really setting the benchmark for other countries around the world who are looking at our NHS antimicrobial subscription model and seeing if they can adopt it to try get the antibiotic pipeline going,” says Howard.

“We might actually get something in the pipeline coming through that could work as well as the fluoroquinolones, so we can have safer drugs moving forward,” he states.

Penicillin allergy de-labelling

One of the main use cases for fluoroquinolones in NICE guidelines is for those with penicillin allergy. According to the British Society for Allergy and Clinical Immunology (BSACI), 5.6% of the population in the UK carry a penicillin allergy label​[21]​. However, around 95% of these labels are incorrect when patients are tested and fewer than 10% of them are likely to have a true allergy​[21,22]​.

Zafar believes correct labelling of penicillin allergy and increasing penicillin allergy de-labelling will have a major impact on use of more harmful alternatives, such as fluoroquinolones.

In September 2023, the Royal Pharmaceutical Society published the penicillin allergy checklist, to increase awareness of the risk of improper labelling and improve reporting of this (See Box 2)​[23]​.

A University of Oxford trial  — ‘ALABAMA‘ — is also underway, which aims to assess the impact of penicillin allergy status on antimicrobial prescribing, patient outcomes and antimicrobial resistance​[24]​. Results of the study are expected to be published in May 2024.

There are still challenges in de-labelling of the allergy, owing to a lack of allergy specialists in England who are required for the task​[25]​. In September 2022, the BSACI published a guideline for the set-up of penicillin allergy de-labelling services by non-allergists working in a hospital setting, but this still requires oversight from an allergy or immunology specialist​[21]​.

Howard stresses the importance of removing incorrect penicillin allergy labels to reduce fluoroquinolone use further, and encourages healthcare professionals to look at the BSACI guideline​[21]​.

On the horizon

Responding to Rehal’s comments around the need for a national audit on fluoroquinolone prescribing, Howard says this is something that needs wider discussion. “There are audits that exists already but by infection rather than drug.

“So having a drug-focused audit is going to be different to what UKHSA has done previously,” he says.

Howard explains that there are many difficulties when trying to get information on prescribing, owing to variability in SNOMED clinical coding completion and different systems across the NHS. “But we’ll come up with audit tools to try and make sure that where we are using it [fluoroquinolones], we’re using it in the safest way possible.”

In the meantime, Howard says NHS England, the UKHSA and NICE are working on providing guidance for alternatives to fluoroquinolones by infection type, which will build on the summary of antimicrobial prescribing guidance. Work is also underway to ensure all guidelines are up to date.

The risk of tendonitis and tendon rupture will always remain with fluoroquinolones. While the government and regulatory bodies work on finding alternative solutions, Rehal says that community pharmacists could have a vital role to play in decreasing the risks of these antibiotics in future.

As community pharmacy gains access to GP clinical systems, it will allow better monitoring of appropriate fluoroquinolone prescribing, he says. “You’ve got a really strong untapped resource there, who can play such an important role.”