Quinolones are a class of broad-spectrum antibiotics that inhibit bacterial DNA synthesis. The addition of a fluorine atom to a quinolone forms a subset of medicines referred to as fluoroquinolones, which have enhanced antimicrobial activity. Fluoroquinolones available in New Zealand include:1 Show
*Formulated with hydrocortisone; indicated for the treatment of otitis externa if Pseudomonas is suspected N.B. Prescribing restrictions, endorsements and Special Authority criteria apply, see Table 1 for details. Quinolones are most active against Gram-negative bacteriaQuinolones are very active against aerobic Gram-negative bacilli and cocci, including Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis (Branhamella catarrhalis) and Neisseria gonorrhoeae . They are generally less active against Gram-positive organisms such as staphylococci and much less active against streptococci such as Streptococcus pneumoniae.2 Quinolones are generally not effective against anaerobic organisms. Moxifloxacin is a later generation quinolone and has greater activity against Gram-positive organisms and atypical organisms than ciprofloxacin or norfloxacin, and is also active against anaerobes.2 Many treatment resistant Streptococcus pneumoniae isolates are susceptible to moxifloxacin, although it is not funded for this indication. Moxifloxacin should not be considered effective against Pseudomonas aeruginosa. While it is not first-line, it does have activity against susceptible methicillin-resistant Staphylococcus aureus.3 There are few indications for use in primary careA restrictive approach to the use of quinolones is recommended as community prescribing of quinolones significantly contributes to antimicrobial resistance (see: “Quinolone resistance is increasing”). Ideally, quinolones should be reserved for serious, life-threatening or difficult-to-treat infections, when other antibiotics cannot be used due to allergy or intolerance, or when the pathogen is resistant to alternative antimicrobial agents (see Table 1). For further information on prescribing quinolones for individual conditions as per Table 1, including dosing and regimen recommendations, see: https://bpac.org.nz/antibiotics/guide.aspx Clinical scenarios where ciprofloxacin is not recommendedCiprofloxacin should not be used for:
Ciprofloxacin is generally not recommended for pyelonephritis, although it is used occasionally. Trimethoprim + sulfamethoxazole is first-line; amoxicillin clavulanate and cefalexin are alternatives.4 N.B. Norfloxacin should not be used for pyelonephritis as it has poor tissue penetration and is no longer recommended for uncomplicated urinary tract infection. Some DHBs have excluded norfloxacin from their formularies as it is no longer considered appropriate due to resistance and safety concerns. Table 1. Indications for quinolones in primary care. N.B. There are no indications for norfloxacin in primary care.1, 4–8
* Ear drops formulated with hydrocortisone (not funded) † Eye drops are subsidised by endorsement when prescribed for the treatment of bacterial keratitis or severe bacterial conjunctivitis resistant to chloramphenicol; or for the second-line treatment of chronic suppurative otitis media (unapproved indication). ** Moxifloxacin can be prescribed fully funded with Special Authority approval for the treatment of M. genitalium infection (unapproved indication). Applications are to be made by a sexual health specialist or on their recommendation. N.B. A similar regimen is likely to be appropriate for persistent cervicitis or severe pelvic inflammatory disease caused by M. genitalium infection. ‡ Consider the underlying cause of relapsing UTI, e.g. a prostatic abscess or renal tract abnormality For further information on Mycoplasma genitalium, see: https://bpac.org.nz/2019/mycoplasma-genitalium.aspx Quinolones are generally well tolerated, with the most common adverse effects resulting from gastrointestinal disturbance, as with most antibiotics. Less frequently, people using quinolones may experience central nervous system effects (e.g. headache, insomnia, dizziness, anxiety, restlessness, tremor), crystalluria*, rash or photosensitivity.18 In rare circumstances, serious adverse effects can occur, including tendinitis and tendon rupture, progression or rupture of an aortic aneurysm or aortic dissection, QT prolongation, retinal detachment, CNS excitation and seizures (see: “Tendinitis and tendon ruptures are a rare adverse effect” and “Caution is required when prescribing quinolones in some patients”).2,19 The risk of serious adverse effects seems to be greater with later generation quinolones (i.e. moxifloxacin) than with earlier generations (i.e. ciprofloxacin and norfloxacin).18 * The formation of crystals in the urine due to poor hydration and urine alkalinity; the condition is usually benign, but there have been reported cases of renal failure associated with crystal precipitation 20, 21 Patients should be advised about the risks so that they can prevent or minimise the impact of any adverse effects if they occur. Advise patients to:
N.B. Prescribers should report adverse reactions to the Centre for Adverse Reactions Monitoring (CARM). Reports can be made through your Adverse Reaction Reporting tool in your patient management system or via a variety of other methods. For further information, see: https://nzphvc.otago.ac.nz/reporting/ Patient information leaflets are available from the New Zealand Formulary: https://www.nzf.org.nz/nzf_70421 Caution is required when prescribing quinolones in some patientsMany of the adverse effects associated with quinolones occur more frequently in people with pre-existing risk factors, or in certain at-risk groups, including older people and those with epilepsy. Older peopleQuinolones should be used at the lowest effective dose in older people for as short a duration as clinically possible, to reduce the development of resistance and adverse effects. Renal function declines consistently with age and ciprofloxacin and norfloxacin doses need to be reduced accordingly to avoid adverse effects. For example, an appropriate oral dose for ciprofloxacin in renal impairment is 250–500 mg, twice daily, if eGFR is 30–60 mL/minute/1.73 m2 or once daily, if eGFR < 30 mL/minute/1.73 m2.1 Many antibiotic classes are associated with adverse CNS effects; these appear to be more common with quinolones than other systemic antimicrobials and are of particular concern in older people.24 Some adverse CNS effects in older people may be attributed to ageing, acute illness, other conditions or other medicines so it is important to consider quinolone use when CNS symptoms are reported. People with epilepsy or a history of CNS disordersQuinolones should be used with caution in people at increased risk of seizures, those with CNS disorders or in patients concurrently using medicines which may lower the seizure threshold, e.g. bupropion, due to the potential for adverse CNS effects.25 The risk of seizures, although very rare, may be increased with concomitant NSAID treatment.25 People at risk of aortic aneurysm or dissectionA similar mechanism relating to collagen degradation with quinolone treatment that leads to tendon rupture (see: “Tendinitis and tendon ruptures are a rare adverse effect“) may occur in the wall of the aorta, contributing to an approximately two-fold increase in the risk of progression or rupture of an aortic aneurysm or aortic dissection within 60 days following treatment.15, 26 This is a rare effect and as of March 2019, no cases were reported in New Zealand.15 Risk factors include:15, 19, 27
Quinolones should only be prescribed to people with these risk factors if there are no suitable alternatives and the benefits of treatment outweigh the potential harms. Patients should be advised to seek urgent medical advice if they develop sudden-onset, severe chest, abdominal or lower back pain during or following treatment.19
Tendinitis and tendon ruptures are a rare adverse effectA number of toxicological studies have confirmed that quinolones damage the collagen within tendons, which on rare occasions can result in tendinitis and tendon rupture, particularly affecting the Achilles tendon with bilateral involvement possible. This can occur even after a single dose of quinolone and the risk can persist for months.22 Tendon rupture has been reported within 48 hours of starting treatment, however, cases have also been reported several months after stopping treatment.22 Risk factors for tendon disorders associated with the use of quinolones include:1, 19, 23
Although this adverse effect is rare (estimated incidence rate 0.14% to 0.40%),22 it is important to remember that:1
Between 2007 and 2012, CARM received 53 reports of tendon disorders associated with quinolone use.14 Over one-third (36%) were reports of tendon ruptures, the remainder were mainly categorised as tendinitis. The majority (83%) of cases were reported in people aged 60 years and over. Medicine interactionsQuinolones can interact with a number of other medicines, such as those that reduce seizure threshold, prolong the QT interval, warfarin and medicines metabolised by common pathways in the liver. For further details on medicines that interact with quinolones, refer to the NZF Stockley’s interactions checker: https://www.nzf.org.nz Quinolones should be used cautiously in patients taking warfarin as these medicines may interact to increase the international normalised ratio (INR) and cause severe bleeding. If a quinolone is the most appropriate treatment option, monitor the INR three days after initiating antibiotic treatment.1 Other at-risk groupsCaution is also required with quinolone use in people with:1
Quinolones are generally not used in childrenQuinolones are not recommended for use in people aged under 18 years as they have been associated with arthropathy and damage to immature cartilage of weight-bearing joints in animal studies.1 There are some specific circumstances, such as pseudomonal infections associated with cystic fibrosis, where the short-term use of ciprofloxacin may be justified in children.28 Quinolones should be avoided in pregnancy and while breastfeedingAll quinolones should be avoided in pregnancy as they have been shown to cause arthropathy in animal studies.1 There are limited data available on the safety of quinolone use while breastfeeding. The manufacturers recommend avoiding use as small amounts are detected in the breast milk.1 Quinolone resistance is increasingAntimicrobial resistance to quinolones is prevalent globally, and includes both Gram-negative and Gram-positive strains. In New Zealand, resistance has been shown in:
Ciprofloxacin and norfloxacin use in New Zealand is decreasingDispensing data from the last five years show that ciprofloxacin and norfloxacin use has been steadily decreasing (Figures 1 A and B). Increased awareness of the harms of quinolone treatment, as well as education on rational use, may help to explain this prescribing trend. There have also been changes to funding endorsement for norfloxacin. Medsafe has published two Prescriber Updates on quinolones since 2012, highlighting the risks of tendon rupture and aortic aneurysm or dissection.14, 15 In 2016, the United States Food and Drug Association revised the warnings for quinolones due to the potential for disabling and potentially permanent adverse effects.16 In 2018, several news media articles on the use and safety of quinolones were published in New Zealand. In most DHBs, ciprofloxacin and norfloxacin dispensing decreased by 25–50% between 2015 and 2019 (Figure 2).17 The only DHB without a decrease in ciprofloxacin and norfloxacin dispensing was West Coast. In 2019, ciprofloxacin and norfloxacin use was highest in Midcentral DHB (17 people per 1,000 population) and lowest in Hutt and Counties Manukau DHBs (7 people per 1,000 population). Figure 1 A and B. Number of patients (per 1,000 enrolled patients) dispensed ciprofloxacin (A) or norfloxacin (B), 2015–2019. Note the different scale on the Y axes. Figure 2. Number of patients (per 1,000 enrolled patients) who were dispensed ciprofloxacin or norfloxacin in 2015 and 2019, by DHB. Moxifloxacin use is increasing, but total numbers are still smallMoxifloxacin is funded with Special Authority approval for active tuberculosis, Mycoplasma genitalium infection and penetrating eye injury. The majority of moxifloxacin prescribing for these indications will occur in secondary care; only applications for M. genitalium can be made by a primary care clinician, but this must be on the recommendation of a sexual health physician. Moxifloxacin use more than doubled between 2015 and 2019, however, the total number of patients dispensed moxifloxacin is still very low (i.e. 251 people in total were dispensed moxifloxacin in 2019) (Figure 3). Moxifloxacin dispensing increased in most DHBs between 2015 and 2019 (Figure 4). The highest dispensing rate in 2019 was in Taranaki DHB (17 people per 100,000 population). Possible reasons for this increase include:
Figure 4. Number of patients (per 100,000 enrolled patients) who were dispensed moxifloxacin in 2015 and 2019, by DHB. Peer group discussion availableA peer group discussion is available that is related to this article. See peer group discussion Peer group discussion sheets are available on our website and aim to provide discussion points for use within your peer group. To claim CPD credits for peer review activities, the RNZCGP requires peer groups to be registered. As with other CPD activities one hour of learning activity equates to one credit. Which patients are at the highest risk of developing tendinitis from the use of quinolones?The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in those taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
Do quinolones cause tendonitis?One well-described and serious adverse event associated with fluoroquinolones is tendinitis and tendon rupture. These injuries can result in long-term sequelae, including chronic pain and mobility restrictions, and may warrant surgical intervention.
Who is at risk for fluoroquinolone toxicity?Prescribers should be aware of the risk factors for fluoroquinolone toxicity including patients over 60 years and patients with comorbidities or interacting drugs. Patients should remain vigilant for symptoms such as tendon or abdominal pain and report these promptly.
Who should not take quinolones?Adverse Effects of Quinolones*
*—Because quinolones have been associated with arthropathy and chondrotoxicity in immature animals, they are not recommended for use in children and adolescents younger than 18 years of age, or in pregnant or breastfeeding women.
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